WO2011124190A2

WO2011124190A2 - Method of producing 4-(2-(substituted)-1-(1-hydroxycyclohexyl)ethyl)phenols by o- demethylation of their methylethers by means of inodorous aromatic thiols

Info

Publication number: WO2011124190A2
Application number: PCT/CZ2011/000032
Authority: WO
Inventors: Stanislav Radl; Ludek Ridvan; Ondrej Klecan; Petr Hruby
Original assignee: Zentiva, K.S.
Priority date: 2010-04-06
Filing date: 2011-04-06
Publication date: 2011-10-13
Also published as: CZ2010262A3; CZ303249B6; WO2011124190A3

Abstract

A method of producing 4-(2-(substituted)-l-(l-hydroxycyclohexyl)ethyl)phenols of general formula (I), wherein the symbols R¹ and R² are hydrogen (H) or methyl (CH₃), by demethylation of their methylethers of general formula (II), wherein symbols R¹ and R² have the same meaning as in formula (I), by heating to 100 to 220 °C with at least one equivalent of an aromatic thiol in the environment of solvents; the reaction is carried out with addition of a base and the aromatic thiol is non- stinking. The term non-stinking means that the stink is only perceptible in concentrations reached in a qualified chemical production in extreme situations only, i.e., for example, above an opened vessel containing the substance; the agent should lack extremely disagreeable "sulphur" character typical of low-molecular compounds containing thiol groups; and even in the above mentioned extreme situations its stink does not exceed intensity of commonly used organic solvents under similar conditions. (Formulae (I), (II)).

Description

Method of producing 4-(2-(substituted)-l-(l-hydroxycyclohexyl)ethyl)phenols by O- demethylation of their methylethers by means of inodorous aromatic thiols

Technical Field

The invention relates to a method of producing 4-(2-(substituted)-l -(l -hydroxycyclohexyl) ethyl)phenols of general formula I

wherein each of the symbols R¹ and R² represents hydrogen (H) or methyl (CH₃), by demethylation of their methylethers of general formula II

wherein the symbols R¹ and R² have the same meaning as in formula (I). State of the Art

The compound (la), wherein R¹ = R² = CH₃, known under the name desvenlafaxine, was approved for treating depression and vasomotor symptoms associated with menopause (Drugs of the Future 2006, 31(4), 304-309).

In patent US 4 535 186, Example 19 describes preparation of (la) by debenzylation of the starting O-benzyldesvenlafaxine (III), Scheme 1.

(III)

The reaction is carried out in high dilution and the product is obtained by evaporating the solution after filtering off the catalyst - palladium on charcoal (Pd/C). The solid evaporation residue, i.e. the desvenlafaxine base, is converted, by action of fumaric acid in an acetone- ethanol mixture, to a salt characterized by the melting point of 140 - 142 °C. Preparation of the desvenlafaxine base by debenzylation is also described in application WO 2008/093142. Main disadvantages of this procedure include commercial unavailability of the starting O- benzyldesvenlafaxine and in its high price, resp.

Thanks to commercial availability of venlafaxine ((Ila), R_\ = R₂ = C¾), the O-demethylation of this compound is the most frequently used procedure of preparing desvenlafaxine, Scheme 2. Generally, the demethylation of aromatic methoxy groups is a very well worked out reaction that can be carried out with a great variety of agents, however, mostly under rather severe conditions. In the case of venlafaxine demethylation, the situation is complicated by presence of the unstable tertiary hydroxyl group and also by presence of the dimethylamino group. Possibilities of commercial utilization of the procedure are thus considerably limited.

Venlafaxine

Scheme 2

In applications WO 00/32555, WO 00/32556 and WO 00/59851, the demethylation of venlafaxine is carried out using lithium diphenylphosphide generated from diphenylphosphine by butyllithium in situ. This procedure has disadvantages of using of toxic derivatives of phosphorus and the necessity of working in high dilution.

Patent US 7 026 508 describes demethylation of venlafaxine by means of trialkylborohydrides, for example, L-selectride. This procedure has disadvantages of high price of the said agents and formation of hazardous side products; this technology is complicated by their disposal.

In patents WO 03/048104 and US 6 673 838, the demethylation of venlafaxine is carried out by action of sodium thiophenolate or sodium dodecanethiolate at temperatures of 150 - 200 °C. The respective salts are either prepared in advance from the corresponding thiols using sodium ethanolate or are generated in situ in the same manner. The reaction is carried out either in ethanol in a pressure vessel, or in PEG-400. The reaction time is strongly dependent on the applied temperature; if sodium dodecanethiolate in PEG 400 at 190 °C is used the time of 2 - 3 hours is sufficient; in ethanol at temperature of 150 °C the reaction time is 2 days. In case of sodium dodecanethiolate, the yields of desvenlafaxine given in the examples fluctuate around 80% -of the theory, whereas, for sodium thiophenolate they are^" 19% only This procedure has, in case of thiophenol, a further disadvantage of an exceptionally intensive odour; from the technological point of view, a further trouble is connected with high temperature necessary for reaching sufficient conversion within several hours.

Application WO 2007/120923 describes demethylation of venlafaxine by means of thiophenol with a catalytic amount of a carbonate at the temperature 190 °C, resulting in a venlafaxine composition containing 93% of this substance and having the 97% purity. The yield is not stated. Nevertheless, the comparative examples present even much worse quality for the products of demethylation obtained by reproduction of the examples from application WO 03/048104 mentioned in the previous paragraph. The application emphasizes advantage of using the base in a catalytic amount from the viewpoint of limitation of side reactions and therewith connected formation of undesirable side products.

In application WO 2009/053731 , the demethylation uses sodium 1 ,2-ethanedithiolate in PEG400, generated from 1 ,2-dithioethane and potassium teri-butoxide in situ. This procedure has a considerable disadvantage of using the very intensively stinking 1 ,2-dithioethane.

Application WO 2009/084038 uses, as the demethylation agent, the sodium salt of thioacetic acid in a dipolar aprotic solvent, for instance, dimethylacetamide or N-methylpyrrolidone, generated from thioglycolic acid and sodium hydride in situ. The reaction itself is carried out at temperatures of 160 - 165 °C until the content of venlafaxine drops below 1% (HPLC), which takes 12 - 48 hours, depending on the procedure.

Another possibility of obtaining desvenlafaxine includes demethylation by means of the cheap sodium thiolate (Na₂S) as described in application WO 2007/071404. The reaction is carried out using anhydrous Na₂S in dipolar aprotic solvents of sufficiently high boiling point, for instance, N-methylpyrrolidone, at the temperature of 145 °C for 30 hours. This procedure has the disadvantage, even at the temperature 145 °C, of a long reaction time and the necessity of using dry Na₂S. The reaction time can be reduced using addition of selenium; however, due to its toxicity, this is connected with great problems in the pharmaceutical production. Another disadvantage includes strong bad smell associated with the performance of this procedure.

Application WO 2009034434 describes a modification of this procedure by using Na₂S together with Me SiCl in the environment of PEG400, wherein sodium trimethylsilylthiolate is formed first, which acts as a demethylation agent.

O-demethylation of N,N-didesmethylvenlafaxine (lib), wherein R¹ = R² = H, which is the last intermediate products of venlafaxine synthesis and, thus, also commercially well available, by similar methods is described in numerous applications, for instance, WO 2007/120923, WO 2008/13995, WO 2008/15584, WO 2008/221356, WO 2009/069601 and WO 2009/234020. The formed N,N,0-tridesmethyl venlafaxine (lb), wherein R¹ = R² = H, can then be converted to desvenlafaxine by usual procedures, Scheme 3.

(lib) (lb) (la)

N V-didesmethylvenlafaxine N,N, O-tridesmethylvenlafaxine desvenalafaxme

Scheme 3

It follows from an analysis of these teachings for a person skilled in the art that, for industrial realization of demethylations of venlafaxine (Ila) to desvenlafaxine (la), of N,N- didesmethylvenlafaxine (lib) to N,N,0-tridesmethylvenlafaxine (lb), and of N- desmethylvenlafaxine ((He), R¹ = H, R² = C¾) to N,( -didesmethylvenIafaxine (Ic), resp., use of a suitable alkali alkyl- or arylthiolate, or an alkali sulphide, in a suitable solvent (that is otherwise, for technical and economic reasons, quite attractive) is only applicable under the condition that such agents could be found among the above-cited ones which would, on one hand, combine their sufficient reactivity with a satisfactory selectivity and, on the other hand, would not only be free of any odour but, under the reaction conditions and during further handling, would also be sufficiently stable so that no disagreeably stinking sulphur substances would be formed during their use. With the only exception of dodecanethiol, all so far used alkyl- and arylthiolates are substances characterized by their distinct disagreeable odour. Moreover, other similarly odorous substances are often formed during their use. While sodium dodecanethiolate does not suffer from any of these disadvantages, its reactivity and, in particular, selectivity are obviously not quite satisfactory for O-demethylations of 4-(2- (substituted)-l -(l-hydroxycyclohexyl) ethyl)phenols of general formula (I).

In classical organic chemistry, many agents containing thiol or thioether groupings are used. In their practical industrial application, however, their disagreeable odour, quite pronounced even in very small concentrations, causes considerable problems. On contrary, the odour of sulphur compounds is sometimes used, for example, in adding these substances (for instance, tert- butylthiol or tetrahydrothiophene) for odorization of natural gas used for heating purposes. It is known that disagreeable odour of linear alkanethiols of formula C¾(CH₂)_nSH decreases with increasing length of the aliphatic chain; finally, dodecanethiol (n = 1 1) is described as a compound practically free of disagreeable odour (Tetrahedron Lett. 2001, 42, 9207).

In several recent years, considerable effort has been paid to development of a suitable substitution of the odorous thiol agents (Kiyoharu Nishide, Shin-ichi Ohsugi, Tetsuo Miyamoto, Kamal Kumar, Manabu Node:„Development of odorless thiols and sulphides and their applications to organic synthesis", Monatshefte 2004, 135, 189; Manabu Node, Tetsuya Kajimoto: „Development of odorless organosulfur reagents and asymmetric reaction using odorless thiols", Heteroatom Chemistry 2007, 18, 572). Dodecanethiol, 4-heptylphenyl- methanethiol, 4-dodecylbenzenethiol, 4-heptylbenzenethiol, 4-tetramethylsilylbenzenethiol, 2- dodecyl-l ,3-propanedithiol, 4-octyloxyphenylmethanethiol, and 4-octyloxybenzenethiol are typical examples of this effort.

This resulted in practice in introduction of 1 -dodecanethiol as a substitute for ethanethiol or other lower alkanethiols for demethylation of aromatic methoxy groups. Moreover, 4- heptylphenylmethanethiol has been developed as a substitute for the odorous benzylmercaptan in the Michael addition to ,β-unsaturated ketones. Up to now, dodecanethiol is also the only inodorous thiol used in demethylation of venlafaxine to desvenlafaxine. It is free of the disagreeable thiol odour and no substances with bad smell are formed during its use under the described conditions. In the same way, other higher thiols CH3(CH2)_nSH, wherein n > 11 , could obviously be used; their practical use is, however, prevented either by their commercial unavailability or by high price. Dodecanethiol has the disadvantage of necessity of working at high temperatures. A question arises of whether using of another homologue would result in higher rate, or in better yield and quality of the product.

The demethylation of aromatic methoxy groups is often successfully performed using benzenethiol (thiophenol) in the presence of bases. Unfortunately, thiophenol belongs to the most stinking thiols. As its utilization in organic chemistry is not limited only to the said demethylations but it is also preferably used, for example, for glycosylation, several inodorous substituted aromatic thiols have been developed (see above). The glycosylation has been successfully performed using, for example, 4-octyloxybenzenethiol (Bioorg. Med. Chem. Lett. 2006, . 16, 5736; Carbohydr. Res. 2005, 340, 2360), 4-heptylbenzenethiol (Carbohydr. Res. 2005, 340, 2360), or 2-methyl-5-ieri-butylbenzenethiol (Nucleosides, Nucleotides, Nucleic Acids 2003, 22, .453; Tetrahedron 2008, 64, 1523; Synlett 2009, 603; J. Org. Chem. 2009, 74, 2508). Nevertheless, the results attained with thiophenol in O-demethylations of 4-(2- (substituted)-l-(l-hydroxycyclohexyl)ethyl)phenylmethylethers of general formula (II) described up to now do not give reasons for optimism in testing other thiophenols in these reactions. However, the authors of the present invention have surprisingly succeeded in finding the conditions under which it is the use of inodorous substituted aromatic thiols what provides a convenient solution of all antagonistic requirements laid on industrial production of 4-(2-(substituted)-l-(l-hydroxycyclohexyl)ethyl)phenols of general formula I.

The present invention provides an advantageous solution of O-demethylation of 4-(2- (substituted)- l-(l-hydroxycyclohexyl)ethyl)phenylmethylethers of general formula II by means of inodorous substituted aromatic thiols in a suitable solvent with addition of a base, industrially applicable in producing high purity desvenlafaxine for pharmaceutical purposes or in obtaining intermediates suitable in production of desvenlafaxine for pharmaceutical purposes.

Disclosure of Invention

The invention comprises a method of producing 4-(2-(substituted)-l-(l-hydroxycyclohexyl) ethyl)phenols of general formula I

wherein each of the symbols R¹ and R² independently represent hydrogen (H) or methyl (CH₃), by demethylation of aylmethylethers of general formula (II)

wherein the symbols R¹ and R² have the same meaning as in formula (I),

or of their salts, by heating to 100-220 °C with at least one equivalent of a non-stinking aromatic thiol with addition of a base in the environment of a solvent or a mixture of solvents.

The method of the present invention is technologically feasible and can be easily managed in terms of labour safety and hygiene and of environmental protection, by demethylation of methylethers of general formula (II), with high yield and purity of the obtained product (I). The essence lies, in surprisingly easy demethylation of starting aromatic methylethers (II) by means of inodorous substituted aromatic thiols, for example, 2-methyl-5-tert- butylbenzenethiol (MTBBT), 4-dodecyloxybenzenethiol, or 4-dodecylbenzenethiol, proceeding with addition of a base at technologically well acceptable temperatures. The selectivity of the substituted thiophenols used and their sufficient reactivity, in a preferable embodiment supported by an alkali carbonate or hydrogencarbonate added in a stoichiometric excess with respect to the charged amount of the inodorous thiophenol used, bring about the reduction of undesirable side reactions and a more easy achievement of an impurities profile meeting the requirements of pharmaceutical production. Detailed Description of Invention

An easy industrial applicability of the thiol agents is conditioned by the prerequisite that they are free of any odour and that no odorous compounds are formed during their using. In case of substituted thiophenols and corresponding arylmethylsulphides, exact relation between their structure and odour is not known; according to the above-mentioned practical aspect, compounds considered inodorous substituted thiophenols are those in which the odour is only noticeable in the concentrations attained in a qualified chemical production only in extreme situations, i.e., for example, above an opened vessel containing the substance. The odour of the agent should further lack the extremely disagreeable„sulphur" character typical of low- molecular compounds containing thiol groups that is well known to every expert or layman who has ever experienced escape of odorized gas; and even in the above-mentioned extreme situations, its odour does not exceed the intensity of commonly used organic solvents under similar conditions. Such agent can for certain be used with usual technical equipment of chemical production without work hygiene being deteriorated or the surroundings of the production being annoyed by bad smell. Surprisingly, it has been found that substitution of the aromatic ring and higher molecular weight of non-stinking substituted thiophenols do not lead to worse reactivity in comparison with the strongly stinking thiophenol alone; on contrary, they have a positive influence on selectivity of the demethylation reaction. In addition, it has been found that difference in substitution of the individual tested compounds does not cause marked differences in their reactivity and selectivity in the demethylation reaction of the studied compounds. Thiophenols suitable for carrying out the procedure according to this invention thus include, in particular, all thiophenols for which it has already been found that they are inodorous, i.e., for example, 2-methyl-5-teri-butylbenzenethiol (MTBBT), 4- dodecyloxybenzene-thiol, 4-dodecylbenzenethiol, 4-octyloxybenzenethiol, 4- heptylbenzenethiol, 4-tetramethylsilylbenzenethiol. Moreover, it can be legitimately assumed that, also for other thiophenols in which suitable substitution of the aromatic ring will result in lack or substantial reduction of disagreeable odour, their applicability as agents for highly selective O-demethylation of methylethers of general formula II can be expected. It can be assumed that such compounds will include all higher homologues of already known inodorous thiophenols, similarly to their isomers containing large groups in a closer position to the sulphur atom or bearing branched substituents instead of linear ones, i.e., for example, 2- heptylbenzenethiol and its homologues, 3 -heptylbenzenethiol and its homologues, 5-methyl-2- ie -butylbenzenethiol or 6-methyl-2-tert-butylbenzenethiol and their homologues, 3- tetramethylsilylbenzenethiol or 2-tetramethylsilylbenzenethiol and their homologues etc., and, in addition, all derivatives of the known compounds and their above-mentioned homologues and isomers, substituted in one or more positions by another carbonaceous or alcoxyl residue.

Three commercially available inodorous aromatic thiols were used in the detailed study of demethylation; these were 2-methyl-5-ieri-butylbenzenethiol (MTBBT), 4- dodecyloxybenzene-thiol and 4-dodecylbenzenethiol under standard conditions (Example 2). The reaction with the selected thiol MTBBT was carried out in N,N-dimethylacetamide, N- methylpyrrolidone and PEG-400, PPG-400, and in the various mono- and di-ethers/esters polyethyleneglycol, diethlyleneglycol, triethyleneglycol, tetraethyleneglycol and dipropyleneglycol (PEG-MME, PEG-DME, DEG-MBE, DEG-DEE, DPG-MEA, TEG-MME, TEG-DME, TTEG, and TTEG- DME) in presence of potassium carbonate at temperatures of 130 ^DC, 150 °C and 175 °C. It has been found that in using the most of the mentioned solvents the demethylation proceeds at an acceptable rate; in all cases, the reaction mixtures were free of undesirable colouring; according to analyses carried out by the method of high-performance liquid chromatography (HPLC), not in a single case were impurities (except a side product - MTBBT- methylsulphide) formed in an aggregate amount exceeding several tenths of percent. Example 1 presents selected data for heating to 150 °C.

The reaction can be performed using at least one equivalent of the respective aromatic thiol, preferably using 1.5 to 5 equivalents of the aromatic thiol, more preferably using 2 to 3 equivalents of the aromatic thiol. The comparison is presented in Example 4.

The reaction can be carried out in suitable solvents, which include ethereal or dipolar aprotic solvents of a suitable boiling point. The ethereal solvents which can be used include, for example, diethyleneglycol, triethyleneglycol, tetraethyleneglycol, their monoethers with CI - C4 alkyl groups, diethers with identical or different CI - C4 groups, monoesters with CI - C5 aliphatic acids or aromatic acids, diesters with CI - C5 aliphatic acids or aromatic acids, or monoethers-monoesters containing the above-mentioned alkyl and acyl groups. Suitable ethereal solvents also include polyethyleneglycols, for instance, PEG-400 or PEG-600, polypropyleneglycols, for instance, PPG-400 and their monoethers, diethers, monoesters, diesters or monoethers-monoesters containing the above-mentioned alkyl and acyl groups. The dipolar aprotic solvents which can be used include NN-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide or sulpholane. Mixtures of ethereal solvents with dipolar aprotic solvents of a suitable boiling point can also be preferably used. Example 1 presents selected data showing that at 150 °C demethylation takes place in a similar extent with both said types of solvents. Concerning processability of reaction mixtures, using of the mixtures of ethereal solvents with dipolar aprotic solvents of appropriate boiling point has proved to be particularly advantageous.

The course of demethylation of venlafaxine by aromatic thiols in the presence of bases depends on the amount of the solvent used to a limited extent only, even though, slight slowing-down of the reaction occurs with higher dilution (Example 8). Thus, the technologically appropriate amount of a solvent mainly depends on consistency and stirring ability of the formed reaction mixture; practically used amount varies, depending on the type of solvent, between 2.5 1 (for instance, NN-dimethylacetamide, N-methylpyrrolidine, mixture of polyethyleneglycol monomethylether 550 and N-methylpyrrolidine) up to 5.0 1 of solvent per 1 kg of venlafaxine hydrochloride (PEG-400, mixture of NN-dimethylacetamide with PEG-600).

Suitable bases include alkali or alkaline earth metal alcoholates (for example, sodium methanolate, potassium methanolate, sodium ethanolate, potassium ethanolate,^" or potassium ieri-butanolate), alkali hydroxides, alkaline earth oxides or hydroxides (for example, magnesium oxide, calcium oxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide). However, using of weaker bases, such as carbonates or hydrogencarbonates (sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate) proved to be the most advantageous. The thiolate can either be prepared in advance from the used thiophenol and base, and then mixed with the used substrate; or it can be generated in situ in the reaction mixture and for the reaction not only free base can be used but, preferably, also salts of venlafaxine, among them preferably, in particular, commercially available hydrochloride. In case 1-dodecanethiol is used in this arrangement, demethylation occurs in a substantially smaller extent (Example 2).

The base can be used in a sub-stoichiometric amount with respect to the charged amount of the used substituted thiophenol; surprisingly, however, it has been found that, unlike procedures used and recommended in the State of the -Art, using of sub-stoichiometric or even catalytic amount of the base is not preferable and does not lead to improved selectivity of the reaction. On contrary, it has been proved that the reaction can preferably be carried out even with an amount of the base stoichiometrically exceeding the amount of the used inodorous thiophenol. Several bases in various solvents (N,N-dimethylacetamide, N-methylpyrrolidone and PEG- 400, PEG MME-550) have been compared. In all cases it has been shown that the best conversion is reached using potassium carbonate, potassium hydrogencarbonate, and cesium carbonate. Selected results are demonstrated in Example 3.

The publication J. - Org. Chem. 67, 2541, 2002 describes using of a' thiophenol in suitable solvents, for instance, N-methylpyrrolidone, in the presence of a catalytic amount of KF for demethylation of methylarylethers. Therefore, this possibility was tested with the desvenlafaxine base and 2-methyl-5-/ert-butylbenzenethiol (MTBBT). The results obtained, however, were not more preferable than those in the case when the system proposed by us, i.e. desmethylvenlafaxine (base or hydrochloride), potassium carbonate and MTBBT, was used (Example 9). The reaction can also be carried out in the presence of phase transfer catalysts, for example, quaternary ammonium salts (tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate), crownethers (for example, 18-crown-6, 15-crown-5), or with addition of some other, salts (alkali fluorides, chlorides, or bromides, magnesium halogenides) as shown in Examples 6 and 7.

The temperature used is an important factor influencing demethylation of venlafaxine by aromatic thiols in the presence of bases. Practically, the reaction can be carried out in the range of 100 °C to 220 °C, preferably at temperatures ranging between 130 °C and 190 °C, more preferably at temperatures of 150 °C to 175 °C. Selected data are shown in Example 8. At the said temperatures, selection of appropriate amounts of the base, aromatic thiol, and solvent can result in complete conversion within 4 to 48 hours; thus, according to possibilities of the enterprise given by the technical parameters of equipment, particularly with respect to the temperature attainable in the reactor, the reaction conditions can be adjusted so that the time of reaction would range between 12 and 16 hours, which is preferable from the operational point of view.

Although the O-demethylation of methylethers of general formula (II) has been studied in details on the substrate (Ila) (venlafaxine), it has been proved that the invented procedure can be just as well used for demethylation of NN-didesmethylvenlafaxine (lib) to Ν,Ν, Ο- tridesmethylvenlafaxine (lb), which was then also converted to desvenlafaxine (la) by a generally known procedure consisting in reductive methylation (Example 22).

Due to the fact that Odesmethylvenlafaxine (la, R¹ = ² = Me; desvenlafaxine), N- desmethylvenlafaxine (lie, R¹ = H, R² = Me), and N, 0-didesmethylvenlafaxine (Ic, R¹ = H, R² = Me) are substantial metabolites of venlafaxine (Ila, R¹ = R² = Me) in humans, a possibility has been examined to apply the conditions of this invention to demethylation ofN- desmethylvenlafaxine that would lead to NO-didesmethylvenlafaxine. The starting N- desmethylvenlafaxine is currently commercially available or can be obtained using procedures described, for example, in the literature (J. Med. Chem. 1990,. 33, 2899-2905; WO 2008/059525; US 2004181093). The procedure described in Example 25 has proved applicability of the procedure according to this invention also to O-demethylation of Ν- desmethylvenlafaxine (lie) to Ν,Ο-didesmethylvenlafaxine (Ic), wherein in both cases R¹ = H and R² = CH₃.

The invention is explained in more detail in the following working examples. These examples, which show the advantageousness of the procedure according to this invention in comparison with the current state of the art, are of exclusively illustrative character and in no way do they limit the scope of this invention.

Working Examples

Example 1 : Preparation of desvenlafaxine - comparison of solvents used

0.1 g of venlafaxine hydrochloride (0.32 mmol), 1 ml of the respective solvent, and 0.25 g of finely triturated anhydrous potassium carbonate were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.25 g of the respective thiol was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then, it was stirred at the temperature of 150 °C. After 4 and 24 hours, samples were taken for high-performance liquid chromatographic (HPLC) analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 1. Table 1 :

VLF = venlafaxine

DVLF = desvenlafaxine

DT = dodecanethiol (mw 202.40)

MTBBT = 2-methyl-5- rt-butylbenzenethiol (mw 180.31) DMAc = N,N-dimethylacetamide

NMP = N-methylpyrrolidone

PEG-400 = polyethyleneglycol (typical mw 400)

PEG MME = PEG monomethylether (typical mw 550) PEG DME = PEG dimethylether (typical mw 250)

PPG-400 = polypropyleneglycol (typical mw 400)

DEG MBE = diethyleneglycol monobutylether (mw 162.23) DEG DEE = diethyleneglycol diethylether (mw 162.23) DPG MEA = dipropyleneglycol methylether acetate (mw 190.24)

TEG MME = triethyleneglycol monomethylether (mw 164.20)

TEG DME = triethyleneglycol dimethylether (mw 178.23)

TTEG = tetraethyleneglycol (mw 194.23)

TTEG DME =* tetraethyleneglycol dimethylether (mw 222.28)

Example 2: Preparation of desvenlafaxine - comparison of various thiols in N,N- dimethylacetamide

0.1 g of venlafaxine hydrochloride (0.32 mmol), 1 ml ofNN-dimethylacetamide, and 0.25 g of finely triturated anhydrous potassium carbonate (1.5 mmol) were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.25 g of the respective thiol was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then it was stirred at temperature of 150 °C. After 4 ^"and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 2.

Table 2:

DBT = dodecylbenzenethiol (mw 278.50)

DOBT = dodecyloxybenzenethiol (mw 294.50)

For other abbreviations see Tab. 1

Example 3: Preparation of desvenlafaxine - comparison of various bases

0.1 g of venlafaxine hydrochloride (0.32 mmol), 1 ml ofNN-dimethylacetamide, and 0.25 g of finely triturated base were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.25 g of 2-methyl-5-iert-butylbenzenethiol (1.4 mmol) was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then, it was stirred at temperature of 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 3.

Table 3:

For abbreviations see Tab. 1

Example 4: Preparation of desvenlafaxine - influence of amount of 2-methyl-5- ter/.butylbenzenethiol (MTBBT)

0.1 g of venlafaxine hydrochloride (0.32 mmol), 1.5 ml of NN-dimethylacetamide, and 0.25 g of finely triturated anhydrous potassium carbonate (1.5 mmol) were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.1 to 0.3 g of MTBBT was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then, it was stirred at temperature of 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 4. Table 4:

For abbreviations see Tab. 1

Example 5 : Preparation of desvenlafaxine - influence of the amount of the base used

0.2 g of venlafaxine hydrochloride (0.64 mmol), 3 ml of NN-dimethylacetamide or N- methylpyrrolidone, and the amount of finely triturated anhydrous potassium carbonate listed in Table 5 (0 - 2.9 mmol) were charged into~ the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.3 g (1.65 mmol) of MTBBT was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for - a short time, flushed with argon, and closed again; then, it was stirred at temperature of 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 5.

Table 5:

For abbreviations see Tab. 1 Example 6: Preparation of desvenlafaxine - influence of addition of ethereal phase transfer catalysts

0.2 g of venlafaxine hydrochloride (0.64 mmol), 2 ml of NN-dimethylacetamide, 0.4 g of finely triturated anhydrous potassium carbonate (3.2 mmol), and the respective amount of the phase transfer catalyst (0.1 g 18-crown-6, 0.1 g of 15-crown-5, 0.5 g PEG-400) were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.3 g (1.7 mmol) of MTBBT was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then, it was stirred at temperature of 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 6. ... -

Table

15- C-5 = 1,4,7,10,13-pentaoxacyclopentadecane, 15-crown-5

16- C-6 = 1,4,7, 10,13, 16-hexaoxacyclooctadecane,18-crown-6

For other abbreviations see Tab. 1

Example 7: Preparation of desvenlafaxine - influence of addition of inorganic salts

0.2 g of venlafaxine hydrochloride (0.64 mmol), 2 ml of NN-dimethylacetamide, 0.4 g of finely triturated anhydrous potassium carbonate (2.2 mmol), and 0.1 g of particular salt ( F, CsF, NaCl, KC1, KBr, MgCl₂, MgBr₂) were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.3 g (1.7 mmol) of MTBBT was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again; then, it was stirred at temperature of 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 7.

Table 7

For abbreviations see Tab. 1

Example 8: Preparation of desvenlafaxine - influence of concentration and temperature " 0.2 g of venlafaxine hydrochloride (0.64 mmol), 2 or 3 ml of N,N-dimethylacetamide, 0.3 g of finely triturated anhydrous potassium carbonate (2.2 mmol) were charged into the reaction vial; the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.3 g (1.7 mmol) of 2-methyl-5-tert.butylbenzenethiol (1.7 mmol) was added, the vial was closed, and the mixture was stirred at 100 °C for 1 hour. The vial was then opened for a short time, flushed with argon, and closed again, and stirred at given temperature. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 8.

Table 8

Temperature

130 °C 140 °C 150 °C 160 °C 170 °C

DMAc 2 ml 3 ml 2 ml 3ml 2 ml 3 ml 2 ml 3 ml 2 ml 3 ml

DVLF 4 h 11 9 25 20 54 51 71 67 77 74 [%]

VLF 8 h 3 16 1 6

[%]

DVLF 8 h 97 84 99 94

[%]

VLF 24 h 50 59 13 17 1 3 0 0 0 0 [%]

DVLF 24 h 50 41 87 83 99 97 100 100 100 100 [%]

For abbreviations see Tab. 1

Example 9: Preparation of desvenlafaxine using alkali fluorides

0.28 g of base of venlafaxine (1 mmol), 3 ml of solvent (DMAc, NMP, or their mixture with PEG-400 1 : 1 v/v), 0.3 g of 2-methyl-5-ieri-butylbenzenethiol (1.7 mmol), KF (6 mg; 0.1 mmol) or CsF (16 mg; 0.1 mmol), or with addition of 18-crown-6 (20 mg) were charged into the reaction vial; the mixture was stirred at 150 °C. After 4 and 24 hours, samples were taken for HPLC analysis; the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). The results are shown in Table 9.

Table 9

VLF 24 h 85 71 84 68 77 61 89 86

DVLF 24h 15 29 16 32 23 39 1 1 14

For abbreviations see Tab. 1

Example 10: Preparation of desvenlafaxine by demethylation of venlafaxine in PEG 400 at

150 °C

Potassium carbonate (5 g, 36 mmol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in PEG-400 (15 ml) and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 5.5 g of MTBBT (30 mmol) was added; the temperature of the reaction mixture was increased to 150 °C within 1 hour; at this temperature, the mixture was stirred under mild flow of nitrogen for 16 hours. The course of the reaction was monitored by HPLC and, after the indicated time, practically quantitative conversion was attained. The mixture was cooled to 80 °C, 30 ml of water was added, pH of the reaction mixture was adjusted to 5 with formic acid, and the mixture was washed with heptane (2 x 10 ml). Then, pH was adjusted with ammonia to 9.5 and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water, and, after drying out, 2.3 g (87 % of theory) of desvenlafaxine was obtained, HPLC purity 98.8 %.

Example 1 1 : Preparation of desvenlafaxine by demethylation of venlafaxine in PEG 400 at

175 °C

Using the procedure of Example 8, sufficient conversion (content of venlafaxine HPLC < 1 %) was reached at temperature of 175 °C within 8 hours. The processing provided 2.2 g (83.5 %), HPLC purity 98.3 %.

Example 12: Preparation of desvenlafaxine by demethylation of venlafaxine in DMAc at 150

°C

Potassium carbonate (5 g, 36 mmol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in N,N-dimethylacetamide (15 ml) and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 5.5 g of MTBBT (30 mmol) was added, the temperature of the reaction mixture was increased to 150 °C within 1 hour, and the mixture was stirred at this temperature under mild flow of nitrogen for 18 hours. The course of the reaction was monitored by HPLC and, after the indicated time, practically quantitative conversion was reached. 30 ml of water was added to the reaction mixture, pH of the reaction mixture was adjusted to a value of 4-5 with 35 % HC1, and the mixture was washed with hexane (2 x 10 ml). Then, pH was adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water, and, after drying out, 2.1 g (80 %) of desvenlafaxine was obtained, HPLC purity 98.7 %.

Example 13: Preparation of desvenlafaxine by demethylation of venlafaxine in mixture of

DMAc and PEG-400 at 150 °C

Potassium carbonate (5 g, 36 mmol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in a mixture ofN,N-dimethylacetamide (7.5 ml) and PEG-400 (7.5 ml), and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 5.5 g of MTBBT (30 mmol) was added, the temperature of the reaction mixture was increased to 150 °C within 1 hour, and the mixture was stirred at this temperature under mild flow of nitrogen for 18 hours. Then, 30 ml of water was added, pH of the reaction mixture was adjusted to a value of 4-5 with 35 % HC1, and the mixture was washed with heptane (2 x 10 ml). Then, pH was adjusted to 9.5 with ammonia, and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water, and, after drying out 1.95 g (74 %) of desvenlafaxine was obtained, HPLC purity 98.7 %.

Example 14: Preparation of desvenlafaxine by demethylation of venlafaxine in mixture of

DMAc and PEG-600 at 150 °C

Using the procedure of Example 11, using PEG-600 instead of PEG-400, 2.2 g (83.5 %) of desvenlafaxine was obtained, HPLC purity 98.4 %. Example 15: Preparation of desvenlafaxine by demethylation of venlafaxine in mixture of DMF and PEG-400 under reflux

Potassium carbonate (5 g, 36 mmol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in a mixture of N,N-dimethylformamide (7.5 ml) and PEG-400 (7.5 ml), and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 5.5 g of MTBBT (30 mmol) was added, and the reaction mixture was refluxed under mild flow of nitrogen for 24 hours. The course of the reaction was monitored by HPLC. After venlafaxine has disappeared from the reaction mixture, 30 ml of water was added, pH of the reaction mixture was adjusted to a value of 4-5 with 35 % HC1, and the mixture was washed with heptane (2 x 10 ml). Then, pH was adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water, and, after drying out, 2.35 g (89 %) of desvenlafaxine was obtained, HPLC purity 98.8 %.

Example 16: Preparation of desvenlafaxine by demethylation of venlafaxine in ΝΜΡ at 150 °C

Potassium carbonate (5 g, 36 mmol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in N-methylpyrrolidone (10 ml) and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 5.5 g of MTBBT (30 mmol) was added, and temperature of the reaction mixture was increased to 150 °C within 1 hour; the mixture was stirred at this temperature under mild flow of nitrogen for 20 hours. Then, 30 ml of water was added, pH of the reaction mixture was adjusted to 5 with 35 % HC1, and the mixture was washed with methyl-te -butylefher (2 x 10 ml). pH was then adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water, and, after drying out, 2.25 g (85 %) of desvenlafaxine was obtained, HPLC purity 98.7 %.

Example 17: Preparation of desvenlafaxine by demethylation of venlafaxine in DMAc at 175

°C

Using the procedure described in Example 12, the reaction was carried out at temperature of 175 °C for 6 hours. After drying out, 2.1 g (80 %) of desvenlafaxine was obtained, HPLC purity 98. %. Example 18: Preparation of desvenlafaxine by demethylation of venlafaxine in PEG-MME at 175 °C

Using the procedure described in Example 12, the reaction was carried out in polyethyleneglycol moriomethylether of typical molar weight of 550 at temperature of 175 °C for 6 hours. After drying out, 2.3 g (87 %) of desvenlafaxine was obtained, HPLC purity 99.4 %.

Example 19: Preparation of desvenlafaxine by demethylation of venlafaxine in DMAc at 190

°C

Using the procedure described in Example 12, the reaction was carried out at temperature of 190 °C for 3 hours. After drying out, 2.1 g (80 %) of desvenlafaxine was obtained, HPLC purity 97.5 %.

Example 20: Preparation of desvenlafaxine by demethylation of venlafaxine in mixture of

PEG-400 and DMAc at 190 °C

Using the procedure described in Example 13, the reaction was carried out at temperature of 190 °C for 4 hours. After drying out, 2.2 g (83.5 %) of desvenlafaxine was obtained, HPLC purity 98.1 %.

Example 21 : Preparation of desvenlafaxine by demethylation of venlafaxine in mixture of PEG

MME and NMP at l90 °C

Potassium carbonate (50 g, 0.36 mol) was added to a solution of venlafaxine hydrochloride (31.4 g, 0.1 mol) in a mixture of polyethyleneglycol monomethylether of typical molar weight 550 (50 ml) and N-methylpyrrolidone (20 ml), and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 25 g of MTBBT (0.14 mol) was added, temperature of the reaction mixture was increased to 190 °C within 1 hour, and the mixture was stirred at this temperature under mild flow of nitrogen for 5 hours. Then, the mixture was stirred without heating so that temperature would decrease to 80 °C within 1 hour; 250 ml of water was added to the mixture and the mixture was stirred for 30 minutes. Then, pH of the reaction mixture was adjusted to 5 with 35 % HCl and the mixture was washed with methyl-ieri-butylether (2 x 50 ml, 2 x 25 ml). Then, pH of the water layer was adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water and cold 2-propanol. After drying out, 23.4 g (88.9 %) of desvenlafaxine was obtained, HPLC purity 99.1 %.

Example 22: Preparation of desvenlafaxine from didesmethylvenlafaxine (lib)

Mild flow of nitrogen was introduced to the flask, and 28.5 g of didesmethylvenlafaxine (0.1 mol) and 100 ml of PEG-400 was added. Then, 50 g of potassium carbonate (0.36 mol) was added and the mixture was stirred under nitrogen at laboratory temperature for 1 hour. Then, 55 g of MTBBT (0.3 mol) was added, temperature of the reaction mixture was increased to 160 °C within 1 hour, and the mixture was stirred at this temperature under mild flow of nitrogen for 14 hours. The course of the reaction was monitored by'HPLC. After cooling down to ca 80 °C, water (300 ml) was added to the suspension, and the upper organic phase was separated. After additional cooling to about 25 °C, the water phase was acidified to pH 3 by means of 85 % formic acid and shaken with methyl-tert-butylether (2 x 100 ml). Then, additional 50 ml of 85 % formic acid and 40 ml of 35 % aqueous formaldehyde was added, and the mixture was stirred under reflux for 8 hours. After cooling down, pH was adjusted to 9 - 10 with aqueous ammonia and the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off, washed with water (50 ml) and cold isopropanol (15 ml). After drying out, 18.9 g (72 %) of desvenlafaxine was obtained, HPLC purity 95.3 %.

Example 23: Preparation of desvenlafaxine by demethylation of venlafaxine hydrochloride Potassium carbonate (6.9 g, 0.05 mol) was added to a solution of venlafaxine hydrochloride (3.14 g, 10 mmol) in polyethyleneglycol monomethylether of typical molar weight 550 (5 or 10 ml), and the mixture was stirred at laboratory temperature for 30 minutes. (In case of experiment II, the mixture of PEG MME and DMAc was used). Then, the mixture was flushed with nitrogen, 3.7 ml or 5.6 ml of MTBBT (0.02 or 0.03 mol) was added, and the temperature of the reaction mixture was increased to 175 °C within 1 hour; at this temperature, the mixture was stirred under mild flow of nitrogen for 24 hours. After 4 and 24 hours, samples for HPLC analysis were taken, the contents of venlafaxine and desvenlafaxine were determined (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration). Then, the mixture was stirred without heating so that temperature would decease to 80 °C within 1 hour; 30 ml of water was added to the mixture and the mixture was stirred for 30 minutes. Then, pH of the reaction mixture was adjusted to 4-5 with 35 % HCl and the mixture was washed with hexane (2 10 ml). Then, pH of the water layer was adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off and washed with water. The product was dried in the air for 12 hours. The results are shown in table 10.

Table 10

Example 24: Preparation of desvenlafaxine by demethylation of venlafaxine hydrochloride

Potassium carbonate (39.3 g, 0.284 mol) was added to a solution of venlafaxine hydrochloride (17.5 g, 55.8 mmol) in polyethyleneglycol monomethylether of typical molar weight 550 (56 ml), and the mixture was stirred at laboratory temperature for 30 minutes. Then, the mixture was flushed with nitrogen, 20.9 ml of MTBBT (0.1137 mol) was added, and temperature of the reaction mixture was increased to 175 °C within 1 hour; at this temperature, the mixture was stirred under mild flow of nitrogen for 9 hours. In the interval of 1 hour, during 6 hours, samples for HPLC were taken; contents of venlafaxine and desvenlafaxine were determined (peaks of solvents, agents, and formed methylthioether were excluded from the integration); the last sample was taken after 9 hours. Then, the mixture was stirred without heating so that temperature would decrease to 80 °C within 1 hour, 180 ml of water were added to the mixture, and the mixture was stirred for 30 minutes. pH of the reaction mixture was adjusted to 4-5 with 35 % HCl and the mixture was washed with hexane (2 x 60 ml). Then, pH of the layer was adjusted to 9.5 with ammonia and, after cooling down, the mixture was stirred at laboratory temperature for 1 hour. The insoluble portion was sucked off and washed with water. The product was dried in the air for 12 hours. 14.3 g (98 %) of desvenlafaxine was obtained, HPLC purity 98.7 %. The results are shown in Table 11.

Table 11

Example 25: Preparation of N.O-didesmethylvenlafaxine by demethylation of N- desmethylvenlafaxine

100 mg of N, Odidesmethylvenlafaxine (0.38 mmol), 2 ml of NN-dimethylacetamide, and 0.2 g of finely triturated anhydrous potassium carbonate (1.4 mmol) were charged into the reaction vial, and the mixture was stirred at laboratory temperature for 10 minutes. Then, 0.2 g of MTBBT (1.1 mmol) was added, the vial was closed and the mixture was stirred at 100 °C for 1 hour. The vial was opened for a short time, flushed with argon, closed again, and stirred at temperature of 150 °C. After 24 hours, according to LC-MS, the mixture contained just a trace amount of the starting N-desmethylvenlafaxine and the main product was Ν,Ο- didesmethylvenlafaxine. HPLC analysis of this sample showed the content of 97.3 % of this main product, 0.2 % of the starting N-desmethylvenlafaxine, and 2.5 % of side products, wherein none of them reached the amount of 0.6 % (the peaks of the solvents, agents, and formed methylthioethers were excluded from the integration).

Claims

1. A method of preparing 4-(2-(substituted)-l-(l-hydroxycyclohexyl) ethyl)phenols of general formula I

wherein each of the symbols R¹ and R² independently represents hydrogen (H) or methyl (CH₃),

by O-demethylation of arylmethylethers of formula II

or of their salts,

wherein Me is CH₃ and each of the symbols R¹ and R² independently represents H or CH₃, by heating to 100 to 220 °C with at least one equivalent of an aromatic thiol in the environment of a solvent, characterized in that the reaction is carried out with addition of a base and the aromatic thiol is inodorous, it being understood by the term non-stinking that the stink is only perceptible at concentrations reached in qualified chemical production in extreme situations only, i.e., for example, above an opened vessel containing the substance; lacks the extremely disagreeable„sulphur" character typical of low-molecular compounds carrying thiol groups; and even in the said extreme situations its stink does not exceed intensity of commonly used organic solvents under similar conditions.

2. The method according to Claim 1, characterized in that the inodorous substituted aromatic thiol is selected form the group consisting of 2-methyl-5-ieri- butylbenzenethiol, 4-dodecylbenzenethiol, 4-dodecyloxybenzenethiol, 4- octyloxybenzenethiol, 4-heptylbenzenethiol or 4-tetramethylsilylbenzenethiol, their homologues, isomers carrying, instead of linear groups, branched groups, and isomers substituted by the same linear or branched groups in positions of the aromatic ring located closer to the sulphur atom, and derivatives of said compounds substituted in one or more additional positions with another carbonaceous or alcoxyl residue.

3. The method according to Claim 1 or 2, characterized in that the inodorous substituted aromatic thiol is 2-methyl-5-tert-butylbenzenethiol, 4-dodecylbenzenethiol, 4-dodecyloxybenzenethiol, 4-octyloxybenzenethiol, 4-heptylbenzenethiol, or 4- tetramethylsilylbenzenethiol.

4. The method according to any one of Claims 1-3, characterized in that the reaction is carried out at a temperature of 130 to 190 °C.

5. The method according to any one of Claims 1-4, characterized in that the reaction is carried out at a temperature of 150 to 175 °C.

6. The method according to any one of Claims 1-5, characterized in that the base is an alkali or alkaline earth metal alcoholate or hydroxide, an alkaline earth oxide, an alkali metal carbonate, or an alkali metal hydrogencarbonate.

7. The method according to any one of Claims 1-6, char act eri zed in that thebase is sodium methanolate, sodium ethanolate, sodium tert-butanolate, potassium tert- butanolate, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium oxide, calcium oxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, or potassium hydrogencarbonate.

8. The method according to any one of Claims 1-7, characterized in that the base is potassium carbonate.

9. The method according to any one of Claims 1-8, characterized in that the base is used in an amount stoichiometrically exceeding the amount of the aromatic thiol used.

10. The method according to any one of Claims 1-9, characterized in that the solvent is selected from the group consisting of NN-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulpholane, polyethyleneglycol PEG-400, polyethyleneglycol PEG-600, polypropyleneglycol PPG- 400, polyethyleneglycol monomethylether, and polyethyleneglycol diethylether.

11. The method according to any one of Claims 1-10, characterized in that the solvent is a mixture of a solvent selected from the group consisting of N,N- dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and sulpholane and a solvent selected from the group consisting of polyethyleneglycol PEG-400, polyethyleneglycol PEG-600, polypropyleneglycol PPG-400, polyethyleneglycol monomethylether, and polyethyleneglycol diethylether.

12. The method according to any one of Claims 1-11, characterized in that the aromatic thiol is used in an amount of one and a half to five equivalents with respect to the starting arylmethylether of formula II.

13. The method according to any one of Claims 1-12, characterized in that the aromatic thiol is used in an amount of two to three equivalents with respect to the starting arylmethylether of formula II.

14. The method according to any one of the preceding Claims, characterized in that the starting arylmethylether of formula II is used in the form of a salt.

15. The method according to Claim 14, characterized in that the salt is hydrochloride.