Title of Invention	A NEW PROCESS FOR THE PREPARATION OF PHENOLIC HYDROXY-SUBSTITUTED COMPOUNDS
Abstract	The invention relates to a process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent pair, in said general formulae R stands for straight chain or branched C1-6 alkyl group; R2 , R3 , R4 , R5 , and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C1-6 alkylearbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R and R together stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the First ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C1-6 alkylcarbonyloxy group in the 17 position -.

Title of Invention

A NEW PROCESS FOR THE PREPARATION OF PHENOLIC HYDROXY-SUBSTITUTED COMPOUNDS

Abstract

The invention relates to a process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent pair, in said general formulae R stands for straight chain or branched C1-6 alkyl group; R2 , R3 , R4 , R5 , and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C1-6 alkylearbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R and R together stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the First ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C1-6 alkylcarbonyloxy group in the 17 position -.

Full Text	A new process for the preparation of phenolic hydroxy-substituted compounds The invention relates to a process for the preparation of a phenolic hydroxy-substituted ompound of the general formula (I) by desalkylation of an alkyl aryl ether of the general 3rmula (H) by treatment with a tMoiirea/aluminium chloride reagent pair. - in said general formulae R stands for straight chain or branched Ci_g alkyl group; R2, R3, R4, R5, and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C]^ alkylcarbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R" and R together may stand for a 5-7 membered ring or a fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the first ring a steroid, preferably an estratricne derivative optionally substituted with an oxo or C]^ alkylcarbonyloxy group in the 17 position -. Since the phenolic hydroxy is susceptible both to oxidation and to nucleophilic reactions, it is usually brought into temporality protected form in the course of the synthesis. Various protective groups are known of which those protecting the hydroxy in the form of an ether, e. g. in the form of alkoxy, particularly methoxy are preferred, since these arc easy-to-prcpare and the protection is broad in scope. The drawback of this method, however, is that protective group can only be removed under drastic reaction conditions. For demethylation of the alkyl aryl ethers various reactions and reagents arc known of which - without the aim of completeness - those used most frequently are listed below: Demethylation of mcthoxybcnzcnc by aluminium chloride (AlClj) was described in 1944. The drawback of this method is that during the reaction poisouous methyl chloride gas developed; what is more, depending on the molar ratio of the starting material and the AICI3, the aromatic ring became methylated to different extent (Baddeley, G.: J. Chem. Soc., p. 330, 1944). Acidic cleavage of die ether bond by hydrogen iodide (HI) (Coombs, M. M. and Roderick, H. R.: Steroids, Vol. 6, p. 841, 1965) or by boron tribromide (BBr3) (Bhatt, M. V. and Kulkarni. S. U.: Synthesis, p. 249, 1983) is also known. However, corrosive properties and high prices of these reagents are against the industrial application of both processes. The regioselective demethylation of polymefhoxy benzaldcliide by aluminium chloride was studied in benzene. The use of benzene, however, makes difficult the industrial application (Paul, E. G. and Wang, P. S.-C: J. Org. Chcm., Vol. 44, p. 2307, 1979). No mention happens in this publication to demediylatiou of alkyl groups other than methyl, neither to the demethylation of fused ring aromatic ethers or steroids. Demethylation by pyridine hydrochloride requires extreme reaction conditions (180- 220 °C) (Groen, M. B. and Zeclen, F. J.: Tetrahedron Letters, Vol. 23, p. 3611, 1982). Regioselective cleavage of ihc ether bond by aluminium iodide (AII3) in acetonrjilc was describee" by Bhatt, M. V. and Babu, J. R. Tetrahedron Letters, Vol. 25, p. 3497, 1984, and the same effect was found by Node. M. et al when they used aluminium chloride/sodium iodide reagent pair (Chem. Pharra. Bull., Vol. 31, p. 4178. 1983). The effect of trimethylsily! iodide reagent [(Me)3Sii) on several ethers was studied by Jung, M E. and Lister, M. A. (J. Org. Chcm . Vol. 42, p. 3761, J 977), while Wir.terfcldt, E. (Synthesis, p. 617, 1975) used diisobutylalumiaium hydride reagent (DIBAH) in his experiments. Stein, R. P. et al used methylmagnesium iodide (MeMgl) for the demethylation of acid sensitive steroids (Tetrahedron, Vol. 26, p 1917 (1970)), while Wunderwaldt, M. et al demethylated 3-methoxyestra-l,3,5(10)-triene derivatives substituted on the D-ring by treatment with a potassium-tert-butoxide/ethanethiol (KOCMe3/EtSH) reagent pair (Z. Chem., Vol. 21, p. 145,1981). In the latter case hexamethylphoshorous triamide (HMPT) was used as solvent. An interesting reagent pair, i. e. a 2,3,11,12-dicyclohexano-1,4,7,10,13,15- hexaoxacyclooctadecane/potassium pair (or otherwise: dicyclohexano-18-crown-6/potassium) was used by Ohsawa, T. et al (Tetrahedron Letters, Vol. 33, p. 5555, 1992) to demethylate anisole-derivatives and the products were obtained with good yields. Andre, J. D. et al demethylated opiate derivatives by using a methanesulfonic acid (MeS03H)/methionine (a-amino-y-methyl-rnercaptobutyric acid) reagent pair with success (Syn. Commun., Vol. 22. p. 2313, 1992). However, the high price of the methanesulfonic acid and that it was used in a 30-fold excess is against its industrial application. Of the processes listed above the best yields for the ether bond cleavage could be achieved when BBr3 in dichloromethane, DEBAH in toluene, as well as when KOCMe3/EtSH or dicyclohexano-18-crown-6/potassium reagent pairs were used. The processes reviewed above are common in that their plant scale realisations are not without difficulties: the reagents are expensive and the reactions require extreme conditions and/or result in poor yields. The application of a "strong acid/weak nucleophil" reagent pair brought a break-through to the ether-desalkylation technique. In the so called Fujita-method a Lewis acid (a metal halogenide) and - as weak nucleophil - EtSH were used. Of the reagent pairs of this type the boron trifluoride diethyl etherate, the AlCls/EtSH and the aluminium bromide (AlBr3)/EtSH gave the most promising results (Node, M. et al: J. Org. Chem., Vol. 45, p. 4275, 1980). Considering the necessary reaction conditions, the safe application of the reagents and last but no least the price of the reagents, it is only the AlCl3/EtSH reagent pair used in the Fujita ether cleavage process which can be realised with proper yield and at reasonable cost in plant scale. Besides the advantages, this process has several drawbacks: the AlChlEtSR reagent pair should be used in 3-6 fold excess based on the amount of the ether to be dernethylated; when the reaction is finished the excess EtSH (which is used also as a solvent for the reaction) and the ethyl methyl thioether (which presumably is formed in the reaction) should be eliminated by oxidation; the thio compounds used and formed in the reaction have low boiling points and have disagreeable odor also in low concentrations, causing additional costs to provide environmentally acceptable operation and any fault of the operation may result in air pollution. To avoid problems arising from the penetrating odor, recently efforts have been made to improve the methods working with alkylthiol and arilthiol reagents to cleave the ether bond. According to Node's version (Node, M. et al: Tetrahedron Letters, Vol. 42, p. 9207, 2001) the penetrating EtSH could be replaced by the odorless 1-dodccanethiol (lauryl mcrcaptan) among others in the Fujita method. This publication mentions only the yield, which is excellent, but no other details arc given. At the first sight the use of the 1-dodecanethiol seems attractive, but when plant scale implication is considered, several questions come up. The 1-dodecanethiol is sparingly soluble in water (0.01 g in 100 g water) but is readily soluble in organic solvents, causing that during the work up of the reaction mixture with an aqueous treatment, it is contained in the same phase as the product, i. e. an additional separation step is necessary to remove it. The same applies to the 1-dodecanc methyl thioether formed in the reaction. On the other hand, the 1-dodecanethiol is a surfactant (a property, inherent in its structure), which may cause difficulties in the phase separation step. The data (reagent, solvent, temperature, time, yield and reference) of the most important reactions for the desalkylation of ethers are shown in Table 1 below. Wherein the references are as listed below: A/ . Baddeley, G.: J. Chem. Soc, p. 330,1944 B/ Coombs, M. M. and Roderick, H. R.: Steroids, Vol. 6, p. 841,1965; a Paul, E. G. and Wang, P. S.-C: J. Org. Chem., Vol. 44, p. 2307,1979 D/ Bhatt,M.V. and Kulkami, S.U.: Synthesis, p. 249,1983; E/ Groen, M. B. and Zeelen, F. J.: Tetrahedron Letters, Vol. 23, p. 3611,1982; F/ Bhatt, M. V. and Babu, J. R.: Tetrahedron Letters, Vol. 25, p. 3497,1984; G/ Node, M. et al: Chem. Pharm. Bull., Vol. 31, p. 4178, 1983; H/ Jung, M. E. and Lister, M. A.: J. Org. Chem., Vol. 42, p. 3761, 1977; 1/ Winterfeldt, E.: Synthesis, p. 617,1975 J/ Stein, R. P. et al: Tetrahedron, Vol. 26, p. 1917,1970; K/ Wunderwald, M. et al: Z. Chem., Vol. 21, p. 145,1981; U Ohsawa, T. et al: Tetrahedron Letters, Vol. 33, p. 5555,1992; M/ Andre, J. D. et al: Syn. Commun., Vol. 22, p. 2313, 1992; N/ Node, M. et al: J. Org. Chem., Vol. 45, p. 4275,1980; O/ Node, M. et al: Tetrahedron Letters, Vol. 42, p. 9207, 2 To sum up the literature data it can be said that the Fujita method is the most suitable for plant scale desalkylation of alkyl aryl ethers (item N in Table 1). This process, however, has an unquestionable disadvantage: the use of the thiol reagents with intense, disagreeable odor. Since in the pharmaceutical industry desalkylation is a frequently used procedure and the processes listed above go with difficulties at plant scale (expensive reagents, extreme reaction conditions, low yield, intensive odor penetrating into die air), our aim is to provide a ' new desalkylation process without the use of alkanethiols,! Our invention is based on that we have found that thiourea and AICI3 form together a reagent pair. It is a colorless and odorless liquid with moderate viscosity which is readily soluble in certain organic solvents (e. g. in dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xilene) while insoluble in 1,1,2,2-tetrachloroethylene. Further experiments showed that the reagent pair containing the thiourea and AICI3 in equimolar amount can dissolve excess of AICI3 too (0.5-1.5 mol AICI3 is present as excess). This is an advantage when said reagent pair is used in a desalkylation process according to the invention; namely we have found that in the thiourea/AlCls reagent pair the sulphur atom acts as a weak nucleophil and is capable of cleaving a methyl group from a mcthoxy, similarly to the AlCls/EtSII reagent. In a pilot experiment the 17ft-acetoxyestr^-l,3,5,(10)-tricnc-3-ol of the formula^(nT), an intermediate used in the manufacture of pharmaceuticals was prepared by the demethylation of 3p-niethoxy-17 J3-acctoxycstra-l,3,5(10>-triene of the formula (IV) / . t . • without the use of an alkancthiol reagent. 't ' The new process according to the invention gives 17P:acetoxiestra-l,3,5(10)tricnc- -3-ol of the formula (III) in good yield and high purity by dcmethylatior. of 3[i-methoxy-17 p- -acetoxyestra-l,3,5(10)-triene of the formula (IV) by treatment with the thiourea/AJCb reagent pair. Next, another steroid, the 3 pMiydroxyestra-l,3,5(10)-triene-17-one of the formula (V), also an intermediate in the manufacture of pharmaceuticals was prepared, by demethylation of the 3p,-methoxyestra-l,3.5(10)-trienc-17-one of the formula (VT), by treatment with thiourea/AlCb reagent pair. hi a study we subjected several other compounds to demethylation by using the thiourea/AlCh reagent pair of the invention and found that the process utilizing thiourea/AlCh can be extended to the preparation of various substituted phenols and naphthols. In all the reactions snidicd the appropriate, phenolic hydroxy-substitutcd compounds were obtained and successfully recovered. Further, we have found that these phenolic hydroxy-substituted compounds can be prepared not only by demethylation but also by dcsalkylation (1. e. by the removal of a LYs alkyl group from the corresponding starting material) by using the thiourea/AlCb reagent pair. Thus, in our experiments we have found that the new deniethylation process using the thiourca/AlCl3 reagent pair for the preparation of 17p-acetoxyestra-l,3-5(10)-trienc-3-ol of the formula (III) can be extended for the preparation of a phenolic hydroxy-substituied compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent pair. - in said general formulae R1 stands for straight chain or branched Ci R'. and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C].fc alkylcarbonyl, straight chain or branched alkyl or - alkoxy, cr aryl group, or R~ and R" together may stand for a 5-7 membered ring or a fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the first ring a steroid, preferably an estratricne derivative optionally substituted with an e.xo or C]_6 alkylcarbonyloxy group in tlie 17 position -. The new process has several advantages, i. e. the products are obtained with good yields and purity; die process is easy to realize in plant scale, can be operated in an environmentally acceptable fashion in a manner not known is the art to avoid the use of substances having disagreeable odor. We have found only one reference concerning the thiourea/AICI3 reagent pair. It's the Soviet patent application No. 603 395 (priority data: 1976. 11. 22 - SU - 2421790) which discloses that burning metals, such as aluminium and magnesium can be extinguished with a "thiourea / aluminium chloride compound" prepared by mixing its components in cquimolar ratio at a temperature below 50 °C; said compound is a homogenous, transparent liquid with moderate viscosity and certain physical characteristics are also given. It is also mentioned that said compound has been previously used in spectroscopy as model substance to detect the existence of chemical association. No mention happens in the technical literature to that by using the thiourea/AlCl3 reagent pair the phenolic hydroxy-substituted compounds of the general formula (I) can be prepared from the aryl a'kyl ethers of the general formula (II) whereby the compound of the general formula (II) is desalkylatcd (or in other words: the phenolic hydroxy of the compound is liberated), nor is mentioned diat the use of me diiourea/AJCb can be advantageous in organic reactions. Accordingly, the object of the invention is process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formuia (II) by treatment with a thiourca/aluminium chloride reagent pair. - in said general formulae R1 stands for straight ciiain or branched Cj^alkyl group; R2, R\ R4, R5, and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, Cj^ alkylcarbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R~ and R together may stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fjscd ring system may constitute with the first ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or Cj.$ aLkylcarbonyloxy group in the 17 position -. In the compounds of the general formula (II) R1 may stand for straight chain or branched Ci-6 alkyl group, such as methyl, ethyl, n-propyl or n-butyl group. In the compounds of the general formulae (I) and (II) R2, R3. R4, R5 and R6 may stand for halogen atom, such as chloride, bromide, iodine or fluorine atom. In the compounds of the general formulae (I) and (II) R2, R3, R4, R5 and R6 when are defined as an alkylcarbonyl group, may mean a straiglit chain or branched Cl-6 alkylcarbonyl group, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, tertiarybutylcarbonyl group. In the compounds of the general formulae (I) and (IT) R2, R3, R4, R5 and Rs when are defined as straight chain or branched Cj.0 alkyl group, may mean e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiarybutyi group. In the compounds of the general formulae (I) and (II) R2, R3, R4, R5 and R6 when are defined as straight chain or branched Ci^j alkoxy group, may mean e. g. methoxy, cthoxy, n propoxy, isopropoxy, n-butoxy, tcrtiarybutoxy group. In the compounds of the general formulae (I) and (II) R2, R3, R\ R5 and R6 may stand for an aryl group, such as a phenyi or benzyl group. In the compounds of the general formulae (I) and (IT) R2, R3 together may stand for an unsaturated or a partially saturated 5-7 membered ring constituting with the original ring a fused ring system, such as naphthalene or 5,6,7,8-tetrahydronaphthalene. When in the compounds of the general formulae (I) and (IT) R7, R3 together may stand for a fused ring system, the fused ring system may constitute with the first ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C\4 alkylcarbonyloxy group in the 17 position; - said alkylcarbonyloxy is a straight or branched Ci-« alkylcarbonyloxy, such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, Lsopropylcarbonyloxy, n-butylcarbonyloxy, tcrtiarybutylcarbonyloxy. Such estratrienc derivative may be e. g. the 17P-acetoxyestra-l,3,5(10)-triene-3-ol of the formula (III) or the 3\|Vhydroxyestra-l,3,5(10)-tricne-17-oncof the formula (V). It is to be mentioned that the 17P-acetoxycstra-l,3,5(10)-triene-3-ol or by other name: estradiol-17{5-acetate of the formula (III) is an early intermediate for the synthesis of estradiol (other name: estra-l,3,5(10)-triene-3,17(J-diol) and ethynylestradiol (other name: 17o-ethynylestra-l,3^(10)-triene-3,17p-diol), which are the estrogenic components of pharmaceutical compositions used for contraception and for the treatment of hormone deficiency. The detailed description of the invention is as follows: The term "room temperature" means a temperature ranging about from 20 °C to 25 °C. The phenolic hydroxy-substituted compounds of the general formula (I) according to the invention are prepared from the alkyl aryl ethers of the general formula (II) usually in such a manner that the thiourea in an amount of 1-3 mol equivalent per ether group is mixed with 1-6 mol equivalent of A1C13. The reaction with the careful exclusion of moisture is«C carried out without the use of a solvent, or in a suitable solvent, such as dichloromcthane, 1,2-dichloroethane, chloroform, benzene, toluene, xilcnc, 1,1,2,2-tctrachlorocthanc, 1,1,2,2-tetrachloroethylene. Tr.t mixture is stirred for a short time at 100 rpm and then to the reagent pair formed (a liquid), 1 mol equivalent amount of the alkyl aryl ether of the general formula (II) is added. The addition order of the reaction components is interchangeable. The reaction mixture is heated to 40-100 °C and is maintained at this temperature for 1-3 hours. Then the mixture is cooled and 5 wt % hydrochloride acid is added. In some cases the product is simply filterable. When the product is remained in a solution, the aqueous layer is extracted by the appropriate solvent, and the organic layer so obtained is washed with alkali, 1-5 wt % sodium hydroxide, sodium carbonate or sodium bicarbonate to rccovere the product The pH of the alkaline aqueous layer is adjusted to be acidic, the precipitated phenolic product is recovered by filtration or if necessary extraction followed by evaporation. The molar ratio of the components in the thiourea/AlCl3 reagent pair used in the process according to the invention is varied from 1:1 to 1:4, preferably from 1:1 to 1:2. In the process according to the invention the thiourea component of the thiourea/AlCh reagent pair generally is used in 1-5 mol equivalent amount, whereas the AlCh component in 1-20 mol equivalent amount based on one ether group present in the alkyl aryl ether of the general formula (11) in question. For the preparation of a phenolic hydroxy-substituted compound of the general formula (1) by the process according to the invention using the thiourea/AlCb reagent pair, suitably a compound of the general formula (II) wherein R! stands for Ci. methyl, ethyl, n-propyl or n-butyl is applied. ' The desalkylation process using the thiourea/AlCl3 reagent pair to prepare a phenolic hydroxy-substituted compound of the general formula (I) from the corresponding alkyl aryl ether of the general formula (IT) can be carried out in the presence of one or more solvents or without the use of a solvent. Suitably the following solvents can be used: dichloromcthanc, 1,2-dicnloroethane, chloroform, benzene, toluene, xilene, 1,1,2,2-tetrachloroethane, 1,1,2,2-tctrachlorocthylene. Although the thiourea/AlCh, a liquid state reagent pair, is insoluble in 1,1,2,2-tetrachloroethylene, in certain cases it is necessary to use said solvent to dissolve the alkyl aryl ether. In such a case the procedure is as follows: ^ The thiourca/AlClj, a liquid state rcagem pair is dissolved e. g. in dichloromethane; to this solution - the alkyl aryl ether dissolved in tetrachloroelhylene is added; or - first the alkyl aryl ether and subsequently the tctrachloroethylene are added. The desalkylation process using the thiourea/AlC!3 reagent pair to prepare a phenolic hydroxy-substituted compound of the general formula (I) from the corresponding alkyl aryl ether of the general formula (II) is performed at a temperature ranging suitably from 0 °C to 130 °C. By carrying out the reaction according to the invention in the presence of the thiourea/AlCl3 reagent pair and organic solvents, preferably dichloromethane and 1,1,2,2-tetrachloroethylene, the 17p-acetoxyestra-l,3,5(10)-triene-3-ol (HI) was successfully prepared by demethylation of 3p-methoxy-17p-acetoxyestra-l,3,5(10)-triene (TV). By carrying out the reaction according to the invention in the presence of the thiourea/AlCb reagent pair and organic solvents, preferably dichloromethane and 1,2-dichloroethane, 3\|}-hydroxyestra-l,3,5(10)-_triene-17-one (V) was also prepared by the demethylation of 3p-methoxyestra-l,3,5(10)-triene-17-one (VI). The invention is further illustrated by the following non-limiting Examples. Example 1 Preparation of 17p-acetoxyestra-l,3,5(10)-triene-3p-ol (IH) by demethylation of 3p-methoxy-17P-acetoxyestra-l,3,5(10)-triene (IV) To 53.3 g (0.4 mol) of dry alurninium chloride 250 ml of dichloromethane was poured, then 22.84 g (0.3 mol) of crystalline thiourea was added in small portions under stirring over 10 minutes. The addition is carried out at room temperature, at the end the temperature of the mixture raises to 30 °C. After stirring the mixture for additional 15 minutes the mixture becomes a transparent olive-drab solution and the temperature returnes to room temperature. Then 32.85 g (0.1 mol) of 3p^methoxy-17p-acetoxyestra-l,3,5(10)-triene of formula (IV) dissolved in 40 ml of dichloromethane is added over 15 minutes raising the reaction temperature to 30 CC. The mixture is heated to reflux and is maintained at this temperature for 4 hours under stirring. The reaction proceeds along with gradual precipitation of the product . in yellow crystals giving the 17fJ-acetoxyestra-l,3,5(10)-triene-3-ol of the formula (III) in . 65-70 % yield. In order to improve the yield and the purity of the product the reaction is continued as follows: To the reaction mixture 200 ml of 1,1,2,2-tetrachloroethylene is added over 5 minutes. The mixture is kept under continuous stirring and the temperature of the mixture is gradually cievated from 40 °C to 75 °C in such a way that first the dichioromethane being present is distilled off at ^0-43 °C After 2-2.5 hours (while 265 ml of dichioromethane is distilled off) the distillation head temperature dropped. At this time the temperature is elevated to 75-80 °C with heating and maintained at mis value for 1 hour, then the mixture is cooled to 30 °C and 200 ml of 5 wt % hydrochloric acid is added in small portions while taking care of that the temperature not to exceed 75 °C. When the addition of the HC1 is finished, the colour of the product changes first from reddish orange to pink and after stirring for additional 30 minutes to white. At this time die reaction mixture is cooled to room temperature, the stirring is stopped and the product is filtered off, washed and dried. The small amount of hydrogen sulfide formed in the reaction is introduced into a trap containing 10 wt % aqueous sodium hydroxide. The reaction gives 29.5 g (93.9 %) of 17p-acctoxycstra-l,3,5(lO)-tricnc-3-ol of the formula (DT) as a white powder. Example 2 Preparation of 3p-hydroxyestrn-l,3>5(10)-triene-17-onc (V) by demcthylation of 3p-methoxyestra-lr3^(10)-triene-17-one(VI) 230 mg (3 mrnol) of thiourea and 560 mg (4.2 mmol) of aluminium chloride are mixed. To the resulting oily liquid 285 mg (1 mmol) of 3P-methoxycstra-l,3,5(10)-triene-17- ■onc (VI) dissolved in 10 ml of dichioromethane is added. The reaction mixture is stirred for 4 hours under reflux, then 10 ml of 1,2-dichloroethane is added over 5 minutes. The temperature of the reaction mixture is gradually elevated from 40 °C to 75 °C under continuous stirring in such a way that first the dichioromethane being present in the mixture is distilled off at 40-43 °C distillation head temperature. Then the mixture is heated to reflux and maintained at reflux temperature (75-80 °C) for 3 hours. After that the mixture is cooled to room temperature and 5 ml of 5 wt % hydrochloric acid is added in small portions while taking care of that the temperature not to exceed 75 °C. When the addition of the HC1 is finished, the colour of the product changes first from reddish orange to pink and after stirring for additional 30 minutes to while. At this time the reaction mixture is cooled to room temperature, the stirring is stopped and the product is filtered off, washed and dried. 150 mg (54 %) of 3p-hydroxycstra-l,3,5(10)-triene-17-one of the formula (V) is obtained as a white powder. Example 3 Preparation of hydroxy benzene by demethylation of ructhoxybenzene To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmo!) of thiourea 2.16 g (20 mmol) of methoxybcnzene is added. The reaction mixture is heated to 90 °C and maintained at this temperature for 1 hour. The mixture is then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is ailded. The mixture is extracted with chloroform, the organic layer is dried over sodium sulfate and evaporated, yielding 1J9 g (95.2 %) of hydroxybenzene. Example 4 Preparation of 2-hydroxynaphthalene by demethylation of 2-methoxynapb.thalene of the formula (VII) To a mixture of 5.32 g (40 mmol) of aluminium diloride and 1.52 g (20 mmol) of tliiourea 3.16 g (20 mmol) of 2-methoxynaphtalcnc of the formula (VII) is added. The reaction mixture is heated to 90 °C and maintained at this temperature for 1 hour. The mixture is then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The precipitated product is filtered, washed and dried to give 2.58 g (89.5 %) of 2- hydroxynaphthalcne. Example 5 Preparation of l-hydroxy-4-methyIbenzene by demetbylation of l-methoxy-4- -mcthylbenzene The method described in Example 3 is applied with the alteration that instead of methoxybenzene 2.44 g (20 ramol) of l-methoxy-4-methylbcnzcnc is used. 2.16 g (100 %)of 1 -hydroxy-4 -methylbeuzene is obtained. ,^- ■-' Example 6 Preparation of l-hydroxy-4-chlorobenzene by demetbylation of l-methoxy-4- -chlorobenzene The method described in Example 3 is applied with the alteration that instead of methoxybenzene 2.85 g (20 mmol) of l-methoxy-4-chlorobenzene is used. 2.47 g (96 %) of l-hydroxy-4-chlorobcnzenc is obtained. Example 7 Preparation of l-hydroxy-2-chlorbenzeue by demetbylation of l-niethoxy-2- -chlorbenzcne The method described in Example 3 is applied with the alteration that instead of nethoxybenzene 2.85 g (20 mmol) of l-methoxy-2-chJoibenzene is used. 2.01 g (78.2 %) of l-hydroxy-2-chlorbenzenc is obtained. Example 8 Preparation of l-bydroxy-2-hromobenzene by demethylation of l-methoxy-2- -bromobenzenc The method described in Example 3 is applied with die alteration that instead of methoxybenzene 3.74 g (20 mmol) of l-methoxy-2-bromobenzene is used. 3.17 g (91.7 %) of l-hydroxy-2-bromobenzcnc is obtained. Example 9 Preparation of l-hydroxy-4-broinobenzenc by demethylation or l-methoxy-4- •bromobenzene The method described in Example 3 is applied with the alteration that instead of methoxybenzcne 3.74 g (20 mmol) of l-methoxy-4-bromobenzene is used. 3.12 g (90.2%) of l-hydroxy-4-bromobenzene is obtained. Example 10 Preparation of l-hydroxy-4-fIuorobenzeue by deuiethylation of l-uietho\y-4- -fluorobcnzcne The method described in Example 3 is applied with the alteration that instead of methoxybenzene 2.52 g (20 mmol) of l-mcthoxy-4-fluorobenzenc is used. 2.15 g (95.8 %) of l-hydroxy-4-fluorobenzene is obtained. Example 11 Preparation of 1-hydroxy-4-nitrobenzeue by demethylation of l-niethoxy-4- -nitrobenzene To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmol) of thiourea 1.53 g (10 mmol) of l-methoxy-4-nitrobenzene is added. The reaction mixture is heated to 40 °C and maintained at this temperature of 2 hours, then cooled to room temperature and 20 ml of 5 wt % hydrocliloric acid is added. The precipitated product is filtered, washed aod dried giving 1.13 g (81.2 %) of l-hydroxy-4-nitrobcnzenc. Example 12 Preparation ofhydroxybenzene by dcscthylation of ethoxybenzene The method described in Example 3 is applied with the alteration that instead of methoxybenzene 2.44 g (20 mmol) of ethoxyben/ene is used. 1.77 g (94.3%) hydroxybenzene is obtained. Kxample 13 Preparation of hydroxybenzene by debutylation of n-butoxybenzene To a mixture of 2.66 g (20 mmol) of aluminium chloride and 0.76 g (10 mmol) of thiourea 1.50 g (10 mmol) of n-butoxybenzene is added. The reaction mixture is heated to 90 °C and maintained at this temperature for 3 hours. The mixture is cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The mixture is stirred for a few minutes, die phases are separated. The aqueous phase is extracted witii 20 ml of dichloromediane. The combined dichloromethane phases are washed with 3 x 10 ml of 5 % aqueous sodium hydroxide. The combined alkaline phases arc acidified with 18 wt % hydrochloric acid and extracted with 3 x 10 ml of dichloromethane. The combined dichloromediane phases are washed with water, dried over sodium sulfate and evaporated to give 0.59 g (62.8 %) of hydroxybenzene. Example 14 Preparation of 1,4-dihydroxybcnzene by desethylation l-hydroxy-4-cthoxybcnzene To a mixture of 2.66 g (20 mmol) ol aluminium chloride and 0.76 g (10 mmol) of thiourea 1.38 g (10 mmol) of l-hydroxy-4-ethoxybcnzcnc is added. The reaction mixture is heated to 90 °C and maintained at this temperature for 3 hours. Then 10 nd of l,l,2,2-tetrachloroethy!ene is added and stining is continued for an additional 1.5 hour at die same temperature. The mixture is then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The mixture is stirred for a few minutes, then the phases are separated. The aqueous phase is extracted witii 10 ml of dichloromethane. To die aqueous layer so obtained 30 ml of cdianol is added, the mixture is concentrated to 5 cd volume and the product precipitates on standing after 2 days yielding 0.27 g '24.5%) of 1,4-dihydroxybenzene. Example 15 Preparation of 2-hydroxybenzoic acid by demethylation of l-carboxy-2-niethoxybenzene The method described in Example 4 is applied with die alteration that instead of 2-methoxynaphthalcne 3.04 g (20 mmol) of l-carboxy-2-mcthoxybenzene is used yielding 2.48 g (S9.9 °h) of 2-hydroxybenzoic acid. Example 16 Preparation of 4-hydroxybenzoic acid by desethylation of l-carboxy-4-ethoxybenzene The method described in Example 4 is applied with 'Jic alteration that instead of 2-methoxynaphthalene 3.32 g (20 mmol) of l-carboxy-4-ethoxybenzene is used yielding 1.86 g (61.2 %) of 4-hydroxybcnzoic acid. Example 17 Preparation of 5,6,7,8-tetrahydro-2-naphtliol by demethylation of 5,6,7,8-tetrahydro-2- •metlioxynaphthalene of the formula (VUI) To a mixture of 5.67 g (42.5 mmol) of aluminium chloride and 2.28 g (30 mmol) of thiourea 1.62 g (10 mmol) of 5,6,7,8-tetrahydro-2-meUioxynaphthalenc is added. The reaction mixture is heated to °0°C and maintained at this tr.mpernnire for 1 hour, then cooled to room temperature, 20 ml of 1,2-dichloroethane is added and the mixture is poured onto 20 ml of 5 wt % hydrochloric acid/ice mixture. The mixture is stirred for a few minutes, then the phases arc separated. The aqueous layer is extracted with 20 ml of 1,2-dichlorocthane. The combined dichloroethane phases are washed with 3 x 10 ml of 5 % aqueous sodium hydroxide. The combined alkaline phases are acidified with 18 wt % hydrochloric acid solution, then extracted with 3 x 10 ml of dichloromethane. The combined dichlorometliane phases are washed with water, dried over sodium sulfate and evaporated yielding 0.S5 g (57.4) of 5,6,7,8-tctrahydro-2-naphthol. Example 18 Preparation of l-oxo-l^,3,4-tetrahydro-6-hydroxynaphthalene by demethylation of l^xo-l.i^-tetrahydro-fi-mcthoxynaphthalene of the formula (IX) To a mixture of 5.67 g (42.5 mmol) of aluminium chloride and 2.28 g (30 mmol) of thiourea 1.76 g (10 mmol) of l-oxo-l,2,3,4-tctrahydro-6-mcthoxynaphthalcne is added. The reaction mixture is heated to 90 CC, maintained at this temperature for 3 hours, then cooled to room temperature and 20 ml of 1,2-dichlorocdiane is added. The mixture is poured to 20 ml of 5 wt % hydrochloric acid and is stirred at 50 °C for 1 hour. The mixture is cooled to loom temperature, the phases are separated and the aqueous layer is extracted with 20 ml of 1,2-dichloroethane. The combined dichlorocthane phases are washed with 3 x 10 ml of 5 wt % aqueous sodium hydroxide solution. The alkaline phases are combined, acidified with 18 wt % hydrochloric acid solution and extracted with 3 x 10 ml of dichloromethane. The combined dichloromcthanc phases are washed with water, dried over sodium sulfate and evaporated yielding 0.63 g (38.8 %) of 1-oxo-1,2,3,4-tetxahydro-6- hydroxynaphthalene. Example 19 reparation of a mixture of 3-hydroxy-4-methoxyacetophenone (X) and 4-hydroxy-3- -methoxyacetophenone (XI) obtained in 1:1 molar ratio by demethylation of 3,4-diinetboxyacetophenone (XII) 1.06 g (8 mmol) of aluminium chloride and 300 n;g (4 nunol) of thiourea arc mixed, the resulting oily liquid is dissolved in 10 ml of dichloromcthanc. To this solution 0.36 g (2 mmol) of 3,4 dimcthoxyacetophenone (XII) dissolved in 5 ml of dichloromethane is added. The reaction mixture is stirred under reflux for 5 hours, then ceded lo room temperature and 5 ml of 5 wt c,h hydrochloric acid is added. The mixture is stirred for a few minutes, the phases are separated and the aqueous layer is extracted with 2 x 5 ml of dichloromcthanc. The combined organic phases arc washed with 3xl0mlof5wt% aqueous sodium hydroxide solution. The alkaline phases are combined, acidified with 18 \vt % hydrochloric acid solution and extracted with 3 x 10 ml of dichloromethane. The combined dichloromethane phases are washed with water, dried over sodium sulfate and evaporated. 0.12 g oil is obtained which solidifies on standing, consisting of 3-hydroxy-4- methoxyacetophenone (X) and 4-hydroxy-3-methoxyacctophenone (XI) in 1:1 molar ratio (yield: 40 %). WE CLAIM: 1. A process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II), - in said general formulae R1 stands for straight chain or branched Cw alkyl group; R2, R3, R4, R5, and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, Cw alkylcarbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R2 and R3 together stand for a 5-7 membered ring or fused ring system; said the 5-7 membered ring may be a partially saturated ring, substituted or unsubstituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the first ring a steroid, further an estratriene derivative substituted or unsubstituted with an oxo or Cw alkylcarbonyloxy group in the 17 position -, wherein desalkylation is carried out with the use of a thiourea/aluminium chloride reagent pair. 2. A process as claimed in claim 1, wherein the thiourea and the aluminium chloride is applied in a molar ratio from 1:1 to 1:4 in the thiourea/aluminium chloride reagent pair. 3. A process as claimed in claim claim 1, wherein the thiourea and the aluminium chloride is applied in a molar ratio from 1:1 to 1:2 in the thiourea/aluminium chloride reagent pair. 4. A process as claimed in any of claims 1 to 3, wherein the starting alkyl aryl ethers of the general formula (II) R1 stands for methyl, ethyl, n-propyl or n-butyl group. 5. A process as claimed in any of claims 1 to 4, wherein the reaction is carried out in the presence of one or more organic solvents or in the absence of a solvent, f j 6. A process as claimed in claim 5, wherein dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xilene, 1,1,2,2-tetrachloroethane, 1,1,2,2-tetrachloroethylene is used as organic solvent. 7. A process as claimed in any of claims 1 to 6, wherein the thiourea present in the thiourea/aluminium chloride reagent pair is used in 1-5 mole equivalent amount per one ether group to be desalkylated present in an alkyl aryl ether of the general formula (II). 8. A process as claimed in any of claims 1 to 7, wherein the aluminium chloride present in the thiourea/aluminium chloride reagent pair is used in 1-20 mole equivalent amount per one ether group to be desalkylated present in an alkyl aryl ether of the general formula (II). 9. A process as claimed in any of claims 1 to 8, wherein the desalkylation is carried out at a temperature ranging from 0 °C to 130 °C. 10. A process as claimed in claim 1, for the preparation of 17p-acetoxyestra-l,3,5(10)-triene-3-ol of the formula (III) by demethylation of 3P-methoxy-17\|3-acetoxyestra-l,3,5(10)-triene of formula (IV), wherein the demethylation is carried out by using thiourea/aluminium chloride reagent pair in the presence of organic solvents. 11. A process as claimed in claim 1, for the preparation of 3p-hydroxyestra-l,3,5(10)-triene-17-one of the formula (V) by demethylation of 3 P-methoxyestra-1,3,5(10)-triene-17-one of the formula (VI), wherein the demethylation is carried out by using thiourea/aluminium chloride reagent pair in the presence of organic solvents. The invention relates to a process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent pair, in said general formulae R stands for straight chain or branched C1-6 alkyl group; R2 , R3 , R4 , R5 , and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C1-6 alkylearbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R and R together stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the First ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C1-6 alkylcarbonyloxy group in the 17 position -.

Full Text

A new process for the preparation of phenolic hydroxy-substituted compounds
The invention relates to a process for the preparation of a phenolic hydroxy-substituted
ompound of the general formula (I) by desalkylation of an alkyl aryl ether of the general
3rmula (H) by treatment with a tMoiirea/aluminium chloride reagent pair.

- in said general formulae R stands for straight chain or branched Ci_g alkyl group; R2, R3, R4,
R5, and R6 have the same or different meanings and stand for hydrogen or halogen atom,
hydroxy, carboxy, nitro, oxo, C]^ alkylcarbonyl, straight chain or branched alkyl or - alkoxy,
or aryl group, or R" and R together may stand for a 5-7 membered ring or a fused ring
system; said 5-7 membered ring may be a partially saturated ring optionally substituted with
an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the

first ring a steroid, preferably an estratricne derivative optionally substituted with an oxo or
C]^ alkylcarbonyloxy group in the 17 position -.
Since the phenolic hydroxy is susceptible both to oxidation and to nucleophilic
reactions, it is usually brought into temporality protected form in the course of the synthesis.
Various protective groups are known of which those protecting the hydroxy in the form of an
ether, e. g. in the form of alkoxy, particularly methoxy are preferred, since these arc
easy-to-prcpare and the protection is broad in scope. The drawback of this method, however,
is that protective group can only be removed under drastic reaction conditions.
For demethylation of the alkyl aryl ethers various reactions and reagents arc known of
which - without the aim of completeness - those used most frequently are listed below:
Demethylation of mcthoxybcnzcnc by aluminium chloride (AlClj) was described in
1944. The drawback of this method is that during the reaction poisouous methyl chloride gas
developed; what is more, depending on the molar ratio of the starting material and the AICI3,
the aromatic ring became methylated to different extent (Baddeley, G.: J. Chem. Soc., p. 330,
1944).
Acidic cleavage of die ether bond by hydrogen iodide (HI) (Coombs, M. M. and
Roderick, H. R.: Steroids, Vol. 6, p. 841, 1965) or by boron tribromide (BBr3) (Bhatt, M. V.
and Kulkarni. S. U.: Synthesis, p. 249, 1983) is also known. However, corrosive properties
and high prices of these reagents are against the industrial application of both processes.
The regioselective demethylation of polymefhoxy benzaldcliide by aluminium chloride
was studied in benzene. The use of benzene, however, makes difficult the industrial
application (Paul, E. G. and Wang, P. S.-C: J. Org. Chcm., Vol. 44, p. 2307, 1979). No
mention happens in this publication to demediylatiou of alkyl groups other than methyl,
neither to the demethylation of fused ring aromatic ethers or steroids.
Demethylation by pyridine hydrochloride requires extreme reaction conditions (180-
220 °C) (Groen, M. B. and Zeclen, F. J.: Tetrahedron Letters, Vol. 23, p. 3611, 1982).
Regioselective cleavage of ihc ether bond by aluminium iodide (AII3) in acetonrjilc
was describee" by Bhatt, M. V. and Babu, J. R. Tetrahedron Letters, Vol. 25, p. 3497, 1984,
and the same effect was found by Node. M. et al when they used aluminium chloride/sodium
iodide reagent pair (Chem. Pharra. Bull., Vol. 31, p. 4178. 1983).
The effect of trimethylsily! iodide reagent [(Me)3Sii) on several ethers was studied by
Jung, M E. and Lister, M. A. (J. Org. Chcm . Vol. 42, p. 3761, J 977), while Wir.terfcldt, E.

(Synthesis, p. 617, 1975) used diisobutylalumiaium hydride reagent (DIBAH) in his
experiments.
Stein, R. P. et al used methylmagnesium iodide (MeMgl) for the demethylation of acid
sensitive steroids (Tetrahedron, Vol. 26, p 1917 (1970)), while Wunderwaldt, M. et al
demethylated 3-methoxyestra-l,3,5(10)-triene derivatives substituted on the D-ring by
treatment with a potassium-tert-butoxide/ethanethiol (KOCMe3/EtSH) reagent pair (Z. Chem.,
Vol. 21, p. 145,1981). In the latter case hexamethylphoshorous triamide (HMPT) was used as
solvent.
An interesting reagent pair, i. e. a 2,3,11,12-dicyclohexano-1,4,7,10,13,15-
hexaoxacyclooctadecane/potassium pair (or otherwise: dicyclohexano-18-crown-6/potassium)
was used by Ohsawa, T. et al (Tetrahedron Letters, Vol. 33, p. 5555, 1992) to demethylate
anisole-derivatives and the products were obtained with good yields.
Andre, J. D. et al demethylated opiate derivatives by using a methanesulfonic acid
(MeS03H)/methionine (a-amino-y-methyl-rnercaptobutyric acid) reagent pair with success
(Syn. Commun., Vol. 22. p. 2313, 1992). However, the high price of the methanesulfonic acid
and that it was used in a 30-fold excess is against its industrial application.
Of the processes listed above the best yields for the ether bond cleavage could be
achieved when BBr3 in dichloromethane, DEBAH in toluene, as well as when KOCMe3/EtSH
or dicyclohexano-18-crown-6/potassium reagent pairs were used.
The processes reviewed above are common in that their plant scale realisations are not
without difficulties: the reagents are expensive and the reactions require extreme conditions
and/or result in poor yields.
The application of a "strong acid/weak nucleophil" reagent pair brought a
break-through to the ether-desalkylation technique. In the so called Fujita-method a Lewis
acid (a metal halogenide) and - as weak nucleophil - EtSH were used.
Of the reagent pairs of this type the boron trifluoride diethyl etherate, the AlCls/EtSH
and the aluminium bromide (AlBr3)/EtSH gave the most promising results (Node, M. et al: J.
Org. Chem., Vol. 45, p. 4275, 1980). Considering the necessary reaction conditions, the safe
application of the reagents and last but no least the price of the reagents, it is only the
AlCl3/EtSH reagent pair used in the Fujita ether cleavage process which can be realised with
proper yield and at reasonable cost in plant scale. Besides the advantages, this process has
several drawbacks: the AlChlEtSR reagent pair should be used in 3-6 fold excess based on

the amount of the ether to be dernethylated; when the reaction is finished the excess EtSH
(which is used also as a solvent for the reaction) and the ethyl methyl thioether (which
presumably is formed in the reaction) should be eliminated by oxidation; the thio compounds
used and formed in the reaction have low boiling points and have disagreeable odor also in
low concentrations, causing additional costs to provide environmentally acceptable operation
and any fault of the operation may result in air pollution.
To avoid problems arising from the penetrating odor, recently efforts have been made
to improve the methods working with alkylthiol and arilthiol reagents to cleave the ether
bond. According to Node's version (Node, M. et al: Tetrahedron Letters, Vol. 42, p. 9207,
2001) the penetrating EtSH could be replaced by the odorless 1-dodccanethiol (lauryl
mcrcaptan) among others in the Fujita method. This publication mentions only the yield,
which is excellent, but no other details arc given.
At the first sight the use of the 1-dodecanethiol seems attractive, but when plant scale
implication is considered, several questions come up. The 1-dodecanethiol is sparingly soluble
in water (0.01 g in 100 g water) but is readily soluble in organic solvents, causing that during
the work up of the reaction mixture with an aqueous treatment, it is contained in the same
phase as the product, i. e. an additional separation step is necessary to remove it. The same
applies to the 1-dodecanc methyl thioether formed in the reaction. On the other hand, the
1-dodecanethiol is a surfactant (a property, inherent in its structure), which may cause
difficulties in the phase separation step.
The data (reagent, solvent, temperature, time, yield and reference) of the most
important reactions for the desalkylation of ethers are shown in Table 1 below.

Wherein the references are as listed below:
A/ . Baddeley, G.: J. Chem. Soc, p. 330,1944
B/ Coombs, M. M. and Roderick, H. R.: Steroids, Vol. 6, p. 841,1965;
a Paul, E. G. and Wang, P. S.-C: J. Org. Chem., Vol. 44, p. 2307,1979
D/ Bhatt,M.V. and Kulkami, S.U.: Synthesis, p. 249,1983;
E/ Groen, M. B. and Zeelen, F. J.: Tetrahedron Letters, Vol. 23, p. 3611,1982;
F/ Bhatt, M. V. and Babu, J. R.: Tetrahedron Letters, Vol. 25, p. 3497,1984;
G/ Node, M. et al: Chem. Pharm. Bull., Vol. 31, p. 4178, 1983;
H/ Jung, M. E. and Lister, M. A.: J. Org. Chem., Vol. 42, p. 3761, 1977;
1/ Winterfeldt, E.: Synthesis, p. 617,1975
J/ Stein, R. P. et al: Tetrahedron, Vol. 26, p. 1917,1970;
K/ Wunderwald, M. et al: Z. Chem., Vol. 21, p. 145,1981;
U Ohsawa, T. et al: Tetrahedron Letters, Vol. 33, p. 5555,1992;
M/ Andre, J. D. et al: Syn. Commun., Vol. 22, p. 2313, 1992;
N/ Node, M. et al: J. Org. Chem., Vol. 45, p. 4275,1980;
O/ Node, M. et al: Tetrahedron Letters, Vol. 42, p. 9207, 2
To sum up the literature data it can be said that the Fujita method is the most suitable
for plant scale desalkylation of alkyl aryl ethers (item N in Table 1). This process, however,
has an unquestionable disadvantage: the use of the thiol reagents with intense, disagreeable
odor.
Since in the pharmaceutical industry desalkylation is a frequently used procedure and
the processes listed above go with difficulties at plant scale (expensive reagents, extreme
reaction conditions, low yield, intensive odor penetrating into die air), our aim is to provide a
' new desalkylation process without the use of alkanethiols,!
Our invention is based on that we have found that thiourea and AICI3 form together a
reagent pair. It is a colorless and odorless liquid with moderate viscosity which is readily
soluble in certain organic solvents (e. g. in dichloromethane, 1,2-dichloroethane, chloroform,
benzene, toluene, xilene) while insoluble in 1,1,2,2-tetrachloroethylene.
Further experiments showed that the reagent pair containing the thiourea and AICI3 in
equimolar amount can dissolve excess of AICI3 too (0.5-1.5 mol AICI3 is present as excess).
This is an advantage when said reagent pair is used in a desalkylation process according to the

invention; namely we have found that in the thiourea/AlCls reagent pair the sulphur atom acts
as a weak nucleophil and is capable of cleaving a methyl group from a mcthoxy, similarly to
the AlCls/EtSII reagent.
In a pilot experiment the 17ft-acetoxyestr^-l,3,5,(10)-tricnc-3-ol of the formula^(nT),
an intermediate used in the manufacture of pharmaceuticals was prepared

by the demethylation of 3p-niethoxy-17 J3-acctoxycstra-l,3,5(10>-triene of the formula (IV) /

. t . •
without the use of an alkancthiol reagent. 't '
The new process according to the invention gives 17P:acetoxiestra-l,3,5(10)tricnc-
-3-ol of the formula (III) in good yield and high purity by dcmethylatior. of 3[i-methoxy-17 p-

-acetoxyestra-l,3,5(10)-triene of the formula (IV) by treatment with the thiourea/AJCb
reagent pair.
Next, another steroid, the 3 pMiydroxyestra-l,3,5(10)-triene-17-one of the formula (V),
also an intermediate in the manufacture of pharmaceuticals was prepared,

by demethylation of the 3p,-methoxyestra-l,3.5(10)-trienc-17-one of the formula (VT), by
treatment with thiourea/AlCb reagent pair.

hi a study we subjected several other compounds to demethylation by using the
thiourea/AlCh reagent pair of the invention and found that the process utilizing
thiourea/AlCh can be extended to the preparation of various substituted phenols and
naphthols. In all the reactions snidicd the appropriate, phenolic hydroxy-substitutcd
compounds were obtained and successfully recovered.
Further, we have found that these phenolic hydroxy-substituted compounds can be
prepared not only by demethylation but also by dcsalkylation (1. e. by the removal of a LYs

alkyl group from the corresponding starting material) by using the thiourea/AlCb reagent
pair.
Thus, in our experiments we have found that the new deniethylation process using the
thiourca/AlCl3 reagent pair for the preparation of 17p-acetoxyestra-l,3-5(10)-trienc-3-ol of
the formula (III) can be extended for the preparation of a phenolic hydroxy-substituied
compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general
formula (II) by treatment with a thiourea/aluminium chloride reagent pair.

- in said general formulae R1 stands for straight chain or branched Ci R'. and R6 have the same or different meanings and stand for hydrogen or halogen atom,
hydroxy, carboxy, nitro, oxo, C].fc alkylcarbonyl, straight chain or branched alkyl or - alkoxy,
cr aryl group, or R~ and R" together may stand for a 5-7 membered ring or a fused ring
system; said 5-7 membered ring may be a partially saturated ring optionally substituted with
an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the

first ring a steroid, preferably an estratricne derivative optionally substituted with an e.xo or
C]_6 alkylcarbonyloxy group in tlie 17 position -.
The new process has several advantages, i. e. the products are obtained with good
yields and purity; die process is easy to realize in plant scale, can be operated in an
environmentally acceptable fashion in a manner not known is the art to avoid the use of
substances having disagreeable odor.
We have found only one reference concerning the thiourea/AICI3 reagent pair. It's the
Soviet patent application No. 603 395 (priority data: 1976. 11. 22 - SU - 2421790) which
discloses that burning metals, such as aluminium and magnesium can be extinguished with a
"thiourea / aluminium chloride compound" prepared by mixing its components in cquimolar
ratio at a temperature below 50 °C; said compound is a homogenous, transparent liquid with
moderate viscosity and certain physical characteristics are also given. It is also mentioned that
said compound has been previously used in spectroscopy as model substance to detect the
existence of chemical association.
No mention happens in the technical literature to that by using the thiourea/AlCl3
reagent pair the phenolic hydroxy-substituted compounds of the general formula (I) can be
prepared from the aryl a'kyl ethers of the general formula (II) whereby the compound of the
general formula (II) is desalkylatcd (or in other words: the phenolic hydroxy of the compound
is liberated), nor is mentioned diat the use of me diiourea/AJCb can be advantageous in
organic reactions.
Accordingly, the object of the invention is process for the preparation of a phenolic
hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl
ether of the general formuia (II) by treatment with a thiourca/aluminium chloride reagent pair.

- in said general formulae R1 stands for straight ciiain or branched Cj^alkyl group; R2, R\ R4,
R5, and R6 have the same or different meanings and stand for hydrogen or halogen atom,
hydroxy, carboxy, nitro, oxo, Cj^ alkylcarbonyl, straight chain or branched alkyl or - alkoxy,
or aryl group, or R~ and R together may stand for a 5-7 membered ring or fused ring system;
said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo
group or can be an unsaturated ring; or said fjscd ring system may constitute with the first
ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or Cj.$
aLkylcarbonyloxy group in the 17 position -.
In the compounds of the general formula (II) R1 may stand for straight chain or
branched Ci-6 alkyl group, such as methyl, ethyl, n-propyl or n-butyl group.
In the compounds of the general formulae (I) and (II) R2, R3. R4, R5 and R6 may stand
for halogen atom, such as chloride, bromide, iodine or fluorine atom.
In the compounds of the general formulae (I) and (II) R2, R3, R4, R5 and R6 when are
defined as an alkylcarbonyl group, may mean a straiglit chain or branched Cl-6 alkylcarbonyl
group, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,
n-butylcarbonyl, tertiarybutylcarbonyl group.
In the compounds of the general formulae (I) and (IT) R2, R3, R4, R5 and Rs when are
defined as straight chain or branched Cj.0 alkyl group, may mean e. g. methyl, ethyl, n-propyl,
isopropyl, n-butyl, tertiarybutyi group.
In the compounds of the general formulae (I) and (II) R2, R3, R4, R5 and R6 when are
defined as straight chain or branched Ci^j alkoxy group, may mean e. g. methoxy, cthoxy,
n propoxy, isopropoxy, n-butoxy, tcrtiarybutoxy group.

In the compounds of the general formulae (I) and (II) R2, R3, R\ R5 and R6 may stand
for an aryl group, such as a phenyi or benzyl group.
In the compounds of the general formulae (I) and (IT) R2, R3 together may stand for an
unsaturated or a partially saturated 5-7 membered ring constituting with the original ring a
fused ring system, such as naphthalene or 5,6,7,8-tetrahydronaphthalene.
When in the compounds of the general formulae (I) and (IT) R7, R3 together may stand
for a fused ring system, the fused ring system may constitute with the first ring a steroid,
preferably an estratriene derivative optionally substituted with an oxo or C\4
alkylcarbonyloxy group in the 17 position; - said alkylcarbonyloxy is a straight or branched
Ci-« alkylcarbonyloxy, such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,
Lsopropylcarbonyloxy, n-butylcarbonyloxy, tcrtiarybutylcarbonyloxy. Such estratrienc
derivative may be e. g. the 17P-acetoxyestra-l,3,5(10)-triene-3-ol of the formula (III) or the
3|Vhydroxyestra-l,3,5(10)-tricne-17-oncof the formula (V).
It is to be mentioned that the 17P-acetoxycstra-l,3,5(10)-triene-3-ol or by other name:
estradiol-17{5-acetate of the formula (III) is an early intermediate for the synthesis of estradiol
(other name: estra-l,3,5(10)-triene-3,17(J-diol) and ethynylestradiol (other name:
17o-ethynylestra-l,3^(10)-triene-3,17p-diol), which are the estrogenic components of
pharmaceutical compositions used for contraception and for the treatment of hormone
deficiency.
The detailed description of the invention is as follows:
The term "room temperature" means a temperature ranging about from 20 °C to 25 °C.
The phenolic hydroxy-substituted compounds of the general formula (I) according to
the invention are prepared from the alkyl aryl ethers of the general formula (II) usually in
such a manner that the thiourea in an amount of 1-3 mol equivalent per ether group is mixed
with 1-6 mol equivalent of A1C13. The reaction with the careful exclusion of moisture is«C
carried out without the use of a solvent, or in a suitable solvent, such as dichloromcthane,
1,2-dichloroethane, chloroform, benzene, toluene, xilcnc, 1,1,2,2-tctrachlorocthanc,
1,1,2,2-tetrachloroethylene. Tr.t mixture is stirred for a short time at 100 rpm and then to the
reagent pair formed (a liquid), 1 mol equivalent amount of the alkyl aryl ether of the general
formula (II) is added.
The addition order of the reaction components is interchangeable.

The reaction mixture is heated to 40-100 °C and is maintained at this temperature for
1-3 hours. Then the mixture is cooled and 5 wt % hydrochloride acid is added. In some cases
the product is simply filterable. When the product is remained in a solution, the aqueous layer
is extracted by the appropriate solvent, and the organic layer so obtained is washed with
alkali, 1-5 wt % sodium hydroxide, sodium carbonate or sodium bicarbonate to rccovere the
product The pH of the alkaline aqueous layer is adjusted to be acidic, the precipitated
phenolic product is recovered by filtration or if necessary extraction followed by evaporation.
The molar ratio of the components in the thiourea/AlCl3 reagent pair used in the
process according to the invention is varied from 1:1 to 1:4, preferably from 1:1 to 1:2.
In the process according to the invention the thiourea component of the thiourea/AlCh
reagent pair generally is used in 1-5 mol equivalent amount, whereas the AlCh component in
1-20 mol equivalent amount based on one ether group present in the alkyl aryl ether of the
general formula (11) in question.
For the preparation of a phenolic hydroxy-substituted compound of the general
formula (1) by the process according to the invention using the thiourea/AlCb reagent pair,
suitably a compound of the general formula (II) wherein R! stands for Ci. methyl, ethyl, n-propyl or n-butyl is applied. '
The desalkylation process using the thiourea/AlCl3 reagent pair to prepare a phenolic
hydroxy-substituted compound of the general formula (I) from the corresponding alkyl aryl
ether of the general formula (IT) can be carried out in the presence of one or more solvents or
without the use of a solvent. Suitably the following solvents can be used: dichloromcthanc,
1,2-dicnloroethane, chloroform, benzene, toluene, xilene, 1,1,2,2-tetrachloroethane,
1,1,2,2-tctrachlorocthylene.
Although the thiourea/AlCh, a liquid state reagent pair, is insoluble in
1,1,2,2-tetrachloroethylene, in certain cases it is necessary to use said solvent to dissolve the
alkyl aryl ether. In such a case the procedure is as follows: ^
The thiourca/AlClj, a liquid state rcagem pair is dissolved e. g. in dichloromethane; to
this solution
- the alkyl aryl ether dissolved in tetrachloroelhylene is added; or
- first the alkyl aryl ether and subsequently the tctrachloroethylene are added.
The desalkylation process using the thiourea/AlC!3 reagent pair to prepare a phenolic
hydroxy-substituted compound of the general formula (I) from the corresponding alkyl aryl

ether of the general formula (II) is performed at a temperature ranging suitably from 0 °C to
130 °C.
By carrying out the reaction according to the invention in the presence of the
thiourea/AlCl3 reagent pair and organic solvents, preferably dichloromethane and
1,1,2,2-tetrachloroethylene, the 17p-acetoxyestra-l,3,5(10)-triene-3-ol (HI) was successfully
prepared by demethylation of 3p-methoxy-17p-acetoxyestra-l,3,5(10)-triene (TV).
By carrying out the reaction according to the invention in the presence of the
thiourea/AlCb reagent pair and organic solvents, preferably dichloromethane and
1,2-dichloroethane, 3|}-hydroxyestra-l,3,5(10)-_triene-17-one (V) was also prepared by the
demethylation of 3p-methoxyestra-l,3,5(10)-triene-17-one (VI).
The invention is further illustrated by the following non-limiting Examples.
Example 1
Preparation of 17p-acetoxyestra-l,3,5(10)-triene-3p-ol (IH) by demethylation of
3p-methoxy-17P-acetoxyestra-l,3,5(10)-triene (IV)
To 53.3 g (0.4 mol) of dry alurninium chloride 250 ml of dichloromethane was poured,
then 22.84 g (0.3 mol) of crystalline thiourea was added in small portions under stirring over
10 minutes. The addition is carried out at room temperature, at the end the temperature of the
mixture raises to 30 °C. After stirring the mixture for additional 15 minutes the mixture
becomes a transparent olive-drab solution and the temperature returnes to room temperature.
Then 32.85 g (0.1 mol) of 3p^methoxy-17p-acetoxyestra-l,3,5(10)-triene of formula (IV)
dissolved in 40 ml of dichloromethane is added over 15 minutes raising the reaction
temperature to 30 CC. The mixture is heated to reflux and is maintained at this temperature for
4 hours under stirring. The reaction proceeds along with gradual precipitation of the product
. in yellow crystals giving the 17fJ-acetoxyestra-l,3,5(10)-triene-3-ol of the formula (III) in
. 65-70 % yield. In order to improve the yield and the purity of the product the reaction is
continued as follows:
To the reaction mixture 200 ml of 1,1,2,2-tetrachloroethylene is added over 5 minutes.
The mixture is kept under continuous stirring and the temperature of the mixture is gradually

cievated from 40 °C to 75 °C in such a way that first the dichioromethane being present is
distilled off at ^0-43 °C After 2-2.5 hours (while 265 ml of dichioromethane is distilled off)
the distillation head temperature dropped. At this time the temperature is elevated to 75-80 °C
with heating and maintained at mis value for 1 hour, then the mixture is cooled to 30 °C and
200 ml of 5 wt % hydrochloric acid is added in small portions while taking care of that the
temperature not to exceed 75 °C. When the addition of the HC1 is finished, the colour of the
product changes first from reddish orange to pink and after stirring for additional 30 minutes
to white. At this time die reaction mixture is cooled to room temperature, the stirring is
stopped and the product is filtered off, washed and dried.
The small amount of hydrogen sulfide formed in the reaction is introduced into a trap
containing 10 wt % aqueous sodium hydroxide.
The reaction gives 29.5 g (93.9 %) of 17p-acctoxycstra-l,3,5(lO)-tricnc-3-ol of the
formula (DT) as a white powder.
Example 2
Preparation of 3p-hydroxyestrn-l,3>5(10)-triene-17-onc (V) by demcthylation of
3p-methoxyestra-lr3^(10)-triene-17-one(VI)
230 mg (3 mrnol) of thiourea and 560 mg (4.2 mmol) of aluminium chloride are
mixed. To the resulting oily liquid 285 mg (1 mmol) of 3P-methoxycstra-l,3,5(10)-triene-17-
■onc (VI) dissolved in 10 ml of dichioromethane is added. The reaction mixture is stirred for 4
hours under reflux, then 10 ml of 1,2-dichloroethane is added over 5 minutes. The
temperature of the reaction mixture is gradually elevated from 40 °C to 75 °C under
continuous stirring in such a way that first the dichioromethane being present in the mixture is
distilled off at 40-43 °C distillation head temperature. Then the mixture is heated to reflux and
maintained at reflux temperature (75-80 °C) for 3 hours. After that the mixture is cooled to
room temperature and 5 ml of 5 wt % hydrochloric acid is added in small portions while
taking care of that the temperature not to exceed 75 °C. When the addition of the HC1 is
finished, the colour of the product changes first from reddish orange to pink and after stirring
for additional 30 minutes to while. At this time the reaction mixture is cooled to room
temperature, the stirring is stopped and the product is filtered off, washed and dried.

150 mg (54 %) of 3p-hydroxycstra-l,3,5(10)-triene-17-one of the formula (V) is
obtained as a white powder.
Example 3
Preparation of hydroxy benzene by demethylation of ructhoxybenzene
To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmo!) of
thiourea 2.16 g (20 mmol) of methoxybcnzene is added. The reaction mixture is heated to
90 °C and maintained at this temperature for 1 hour. The mixture is then cooled to room
temperature and 20 ml of 5 wt % hydrochloric acid is ailded. The mixture is extracted with
chloroform, the organic layer is dried over sodium sulfate and evaporated, yielding 1J9 g
(95.2 %) of hydroxybenzene.
Example 4
Preparation of 2-hydroxynaphthalene by demethylation of 2-methoxynapb.thalene of the
formula (VII)

To a mixture of 5.32 g (40 mmol) of aluminium diloride and 1.52 g (20 mmol) of
tliiourea 3.16 g (20 mmol) of 2-methoxynaphtalcnc of the formula (VII) is added. The
reaction mixture is heated to 90 °C and maintained at this temperature for 1 hour. The mixture
is then cooled to room temperature and 20 ml of 5 wt % hydrochloric acid is added. The
precipitated product is filtered, washed and dried to give 2.58 g (89.5 %) of 2-
hydroxynaphthalcne.

Example 5
Preparation of l-hydroxy-4-methyIbenzene by demetbylation of l-methoxy-4-
-mcthylbenzene
The method described in Example 3 is applied with the alteration that instead of
methoxybenzene 2.44 g (20 ramol) of l-methoxy-4-methylbcnzcnc is used.
2.16 g (100 %)of 1 -hydroxy-4 -methylbeuzene is obtained. ,^- ■-'
Example 6
Preparation of l-hydroxy-4-chlorobenzene by demetbylation of l-methoxy-4-
-chlorobenzene
The method described in Example 3 is applied with the alteration that instead of
methoxybenzene 2.85 g (20 mmol) of l-methoxy-4-chlorobenzene is used.
2.47 g (96 %) of l-hydroxy-4-chlorobcnzenc is obtained.
Example 7
Preparation of l-hydroxy-2-chlorbenzeue by demetbylation of l-niethoxy-2-
-chlorbenzcne
The method described in Example 3 is applied with the alteration that instead of
nethoxybenzene 2.85 g (20 mmol) of l-methoxy-2-chJoibenzene is used.
2.01 g (78.2 %) of l-hydroxy-2-chlorbenzenc is obtained.
Example 8
Preparation of l-bydroxy-2-hromobenzene by demethylation of l-methoxy-2-
-bromobenzenc
The method described in Example 3 is applied with die alteration that instead of
methoxybenzene 3.74 g (20 mmol) of l-methoxy-2-bromobenzene is used.
3.17 g (91.7 %) of l-hydroxy-2-bromobenzcnc is obtained.

Example 9
Preparation of l-hydroxy-4-broinobenzenc by demethylation or l-methoxy-4-
•bromobenzene
The method described in Example 3 is applied with the alteration that instead of
methoxybenzcne 3.74 g (20 mmol) of l-methoxy-4-bromobenzene is used.
3.12 g (90.2%) of l-hydroxy-4-bromobenzene is obtained.
Example 10
Preparation of l-hydroxy-4-fIuorobenzeue by deuiethylation of l-uietho\y-4-
-fluorobcnzcne
The method described in Example 3 is applied with the alteration that instead of
methoxybenzene 2.52 g (20 mmol) of l-mcthoxy-4-fluorobenzenc is used.
2.15 g (95.8 %) of l-hydroxy-4-fluorobenzene is obtained.
Example 11
Preparation of 1-hydroxy-4-nitrobenzeue by demethylation of l-niethoxy-4-
-nitrobenzene
To a mixture of 5.32 g (40 mmol) of aluminium chloride and 1.52 g (20 mmol) of
thiourea 1.53 g (10 mmol) of l-methoxy-4-nitrobenzene is added. The reaction mixture is
heated to 40 °C and maintained at this temperature of 2 hours, then cooled to room
temperature and 20 ml of 5 wt % hydrocliloric acid is added. The precipitated product is
filtered, washed aod dried giving 1.13 g (81.2 %) of l-hydroxy-4-nitrobcnzenc.
Example 12
Preparation ofhydroxybenzene by dcscthylation of ethoxybenzene
The method described in Example 3 is applied with the alteration that instead of
methoxybenzene 2.44 g (20 mmol) of ethoxyben/ene is used.
1.77 g (94.3%) hydroxybenzene is obtained.

Kxample 13
Preparation of hydroxybenzene by debutylation of n-butoxybenzene
To a mixture of 2.66 g (20 mmol) of aluminium chloride and 0.76 g (10 mmol) of
thiourea 1.50 g (10 mmol) of n-butoxybenzene is added. The reaction mixture is heated to
90 °C and maintained at this temperature for 3 hours. The mixture is cooled to room
temperature and 20 ml of 5 wt % hydrochloric acid is added. The mixture is stirred for a few
minutes, die phases are separated. The aqueous phase is extracted witii 20 ml of
dichloromediane. The combined dichloromethane phases are washed with 3 x 10 ml of 5 %
aqueous sodium hydroxide. The combined alkaline phases arc acidified with 18 wt %
hydrochloric acid and extracted with 3 x 10 ml of dichloromethane. The combined
dichloromediane phases are washed with water, dried over sodium sulfate and evaporated to
give 0.59 g (62.8 %) of hydroxybenzene.
Example 14
Preparation of 1,4-dihydroxybcnzene by desethylation l-hydroxy-4-cthoxybcnzene
To a mixture of 2.66 g (20 mmol) ol aluminium chloride and 0.76 g (10 mmol) of
thiourea 1.38 g (10 mmol) of l-hydroxy-4-ethoxybcnzcnc is added. The reaction mixture is
heated to 90 °C and maintained at this temperature for 3 hours. Then 10 nd of
l,l,2,2-tetrachloroethy!ene is added and stining is continued for an additional 1.5 hour at die
same temperature. The mixture is then cooled to room temperature and 20 ml of 5 wt %
hydrochloric acid is added.
The mixture is stirred for a few minutes, then the phases are separated. The aqueous
phase is extracted witii 10 ml of dichloromethane. To die aqueous layer so obtained 30 ml of
cdianol is added, the mixture is concentrated to 5 cd volume and the product precipitates on
standing after 2 days yielding 0.27 g '24.5%) of 1,4-dihydroxybenzene.
Example 15
Preparation of 2-hydroxybenzoic acid by demethylation of l-carboxy-2-niethoxybenzene
The method described in Example 4 is applied with die alteration that instead of
2-methoxynaphthalcne 3.04 g (20 mmol) of l-carboxy-2-mcthoxybenzene is used yielding
2.48 g (S9.9 °h) of 2-hydroxybenzoic acid.

Example 16
Preparation of 4-hydroxybenzoic acid by desethylation of l-carboxy-4-ethoxybenzene
The method described in Example 4 is applied with 'Jic alteration that instead of
2-methoxynaphthalene 3.32 g (20 mmol) of l-carboxy-4-ethoxybenzene is used yielding
1.86 g (61.2 %) of 4-hydroxybcnzoic acid.
Example 17
Preparation of 5,6,7,8-tetrahydro-2-naphtliol by demethylation of 5,6,7,8-tetrahydro-2-
•metlioxynaphthalene of the formula (VUI)

To a mixture of 5.67 g (42.5 mmol) of aluminium chloride and 2.28 g (30 mmol) of
thiourea 1.62 g (10 mmol) of 5,6,7,8-tetrahydro-2-meUioxynaphthalenc is added. The reaction
mixture is heated to °0°C and maintained at this tr.mpernnire for 1 hour, then cooled to room
temperature, 20 ml of 1,2-dichloroethane is added and the mixture is poured onto 20 ml of 5
wt % hydrochloric acid/ice mixture.
The mixture is stirred for a few minutes, then the phases arc separated. The aqueous
layer is extracted with 20 ml of 1,2-dichlorocthane. The combined dichloroethane phases are
washed with 3 x 10 ml of 5 % aqueous sodium hydroxide. The combined alkaline phases are
acidified with 18 wt % hydrochloric acid solution, then extracted with 3 x 10 ml of
dichloromethane. The combined dichlorometliane phases are washed with water, dried over
sodium sulfate and evaporated yielding 0.S5 g (57.4) of 5,6,7,8-tctrahydro-2-naphthol.

Example 18
Preparation of l-oxo-l^,3,4-tetrahydro-6-hydroxynaphthalene by demethylation of
l^xo-l.i^-tetrahydro-fi-mcthoxynaphthalene of the formula (IX)

To a mixture of 5.67 g (42.5 mmol) of aluminium chloride and 2.28 g (30 mmol) of
thiourea 1.76 g (10 mmol) of l-oxo-l,2,3,4-tctrahydro-6-mcthoxynaphthalcne is added. The
reaction mixture is heated to 90 CC, maintained at this temperature for 3 hours, then cooled to
room temperature and 20 ml of 1,2-dichlorocdiane is added. The mixture is poured to 20 ml
of 5 wt % hydrochloric acid and is stirred at 50 °C for 1 hour.
The mixture is cooled to loom temperature, the phases are separated and the aqueous
layer is extracted with 20 ml of 1,2-dichloroethane. The combined dichlorocthane phases are
washed with 3 x 10 ml of 5 wt % aqueous sodium hydroxide solution. The alkaline phases are
combined, acidified with 18 wt % hydrochloric acid solution and extracted with 3 x 10 ml of
dichloromethane. The combined dichloromcthanc phases are washed with water, dried over
sodium sulfate and evaporated yielding 0.63 g (38.8 %) of 1-oxo-1,2,3,4-tetxahydro-6-
hydroxynaphthalene.

Example 19
reparation of a mixture of 3-hydroxy-4-methoxyacetophenone (X) and 4-hydroxy-3-
-methoxyacetophenone (XI) obtained in 1:1 molar ratio by demethylation of
3,4-diinetboxyacetophenone (XII)

1.06 g (8 mmol) of aluminium chloride and 300 n;g (4 nunol) of thiourea arc mixed,
the resulting oily liquid is dissolved in 10 ml of dichloromcthanc. To this solution 0.36 g
(2 mmol) of 3,4 dimcthoxyacetophenone (XII) dissolved in 5 ml of dichloromethane is
added. The reaction mixture is stirred under reflux for 5 hours, then ceded lo room
temperature and 5 ml of 5 wt c,h hydrochloric acid is added.

The mixture is stirred for a few minutes, the phases are separated and the aqueous
layer is extracted with 2 x 5 ml of dichloromcthanc. The combined organic phases arc washed
with 3xl0mlof5wt% aqueous sodium hydroxide solution. The alkaline phases are
combined, acidified with 18 \vt % hydrochloric acid solution and extracted with 3 x 10 ml of
dichloromethane. The combined dichloromethane phases are washed with water, dried over
sodium sulfate and evaporated.
0.12 g oil is obtained which solidifies on standing, consisting of 3-hydroxy-4-
methoxyacetophenone (X) and 4-hydroxy-3-methoxyacctophenone (XI) in 1:1 molar ratio
(yield: 40 %).

WE CLAIM:
1. A process for the preparation of a phenolic hydroxy-substituted compound of the general formula
(I) by desalkylation of an alkyl aryl ether of the general formula (II),

- in said general formulae R1 stands for straight chain or branched Cw alkyl group; R2, R3, R4, R5,
and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy,
carboxy, nitro, oxo, Cw alkylcarbonyl, straight chain or branched alkyl or - alkoxy, or aryl group,
or R2 and R3 together stand for a 5-7 membered ring or fused ring system; said the 5-7 membered
ring may be a partially saturated ring, substituted or unsubstituted with an oxo group or can be an
unsaturated ring; or said fused ring system may constitute with the first ring a steroid, further an
estratriene derivative substituted or unsubstituted with an oxo or Cw alkylcarbonyloxy group in
the 17 position -, wherein desalkylation is carried out with the use of a thiourea/aluminium
chloride reagent pair.

2. A process as claimed in claim 1, wherein the thiourea and the aluminium chloride is applied in a
molar ratio from 1:1 to 1:4 in the thiourea/aluminium chloride reagent pair.
3. A process as claimed in claim claim 1, wherein the thiourea and the aluminium chloride is
applied in a molar ratio from 1:1 to 1:2 in the thiourea/aluminium chloride reagent pair.
4. A process as claimed in any of claims 1 to 3, wherein the starting alkyl aryl ethers of the general
formula (II) R1 stands for methyl, ethyl, n-propyl or n-butyl group.
5. A process as claimed in any of claims 1 to 4, wherein the reaction is carried out in the presence
of one or more organic solvents or in the absence of a solvent, f j
6. A process as claimed in claim 5, wherein dichloromethane, 1,2-dichloroethane, chloroform,
benzene, toluene, xilene, 1,1,2,2-tetrachloroethane, 1,1,2,2-tetrachloroethylene is used as organic
solvent.
7. A process as claimed in any of claims 1 to 6, wherein the thiourea present in the
thiourea/aluminium chloride reagent pair is used in 1-5 mole equivalent amount per one ether group to
be desalkylated present in an alkyl aryl ether of the general formula (II).
8. A process as claimed in any of claims 1 to 7, wherein the aluminium chloride present in the
thiourea/aluminium chloride reagent pair is used in 1-20 mole equivalent amount per one ether group to
be desalkylated present in an alkyl aryl ether of the general formula (II).
9. A process as claimed in any of claims 1 to 8, wherein the desalkylation is carried out at a
temperature ranging from 0 °C to 130 °C.
10. A process as claimed in claim 1, for the preparation of 17p-acetoxyestra-l,3,5(10)-triene-3-ol of
the formula (III) by demethylation of 3P-methoxy-17|3-acetoxyestra-l,3,5(10)-triene of formula (IV),
wherein the demethylation is carried out by using thiourea/aluminium chloride reagent pair in the
presence of organic solvents.

11. A process as claimed in claim 1, for the preparation of 3p-hydroxyestra-l,3,5(10)-triene-17-one
of the formula (V) by demethylation of 3 P-methoxyestra-1,3,5(10)-triene-17-one of the formula (VI),
wherein the demethylation is carried out by using thiourea/aluminium chloride reagent pair in the
presence of organic solvents.

The invention relates to a process for the preparation of a phenolic hydroxy-substituted compound of the general
formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent
pair, in said general formulae R stands for straight chain or branched C1-6 alkyl group; R2 , R3 , R4 , R5 , and R6 have the same or different
meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C1-6 alkylearbonyl, straight chain or branched
alkyl or - alkoxy, or aryl group, or R and R together stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring
may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may
constitute with the First ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C1-6 alkylcarbonyloxy
group in the 17 position -.

Documents:

02125-kolnp-2007-abstract.pdf

02125-kolnp-2007-assignment.pdf

02125-kolnp-2007-claims.pdf

02125-kolnp-2007-correspondence others 1.1.pdf

02125-kolnp-2007-correspondence others 1.2.pdf

02125-kolnp-2007-correspondence others.pdf

02125-kolnp-2007-description complete.pdf

02125-kolnp-2007-form 1.pdf

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02125-kolnp-2007-form 3 1.1.pdf

02125-kolnp-2007-form 3.pdf

02125-kolnp-2007-form 5.pdf

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02125-kolnp-2007-international publication.pdf

02125-kolnp-2007-international search report.pdf

02125-kolnp-2007-pct request form.pdf

02125-kolnp-2007-priority document.pdf

2125-KOLNP-2007-ABSTRACT 1.1.pdf

2125-KOLNP-2007-ABSTRACT.pdf

2125-KOLNP-2007-AMANDED CLAIMS 1.1.pdf

2125-KOLNP-2007-AMANDED CLAIMS.pdf

2125-KOLNP-2007-ASSIGNMENT.1.2.pdf

2125-KOLNP-2007-CORRESPONDENCE 1.1.pdf

2125-KOLNP-2007-CORRESPONDENCE.1.2.pdf

2125-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

2125-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

2125-KOLNP-2007-EXAMINATION REPORT.1.2.pdf

2125-KOLNP-2007-FORM 1 1.1.pdf

2125-KOLNP-2007-FORM 1.pdf

2125-KOLNP-2007-FORM 18.1.2.pdf

2125-KOLNP-2007-FORM 2 1.1.pdf

2125-KOLNP-2007-FORM 2.pdf

2125-KOLNP-2007-FORM 3.1.2.pdf

2125-KOLNP-2007-FORM 3.pdf

2125-KOLNP-2007-FORM 5.1.2.pdf

2125-KOLNP-2007-GPA.1.2.pdf

2125-KOLNP-2007-GRANTED-ABSTRACT.pdf

2125-KOLNP-2007-GRANTED-CLAIMS.pdf

2125-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

2125-KOLNP-2007-GRANTED-FORM 1.pdf

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2125-KOLNP-2007-GRANTED-SPECIFICATION.pdf

2125-KOLNP-2007-OTHERS 1.1.pdf

2125-KOLNP-2007-OTHERS.1.2.pdf

2125-KOLNP-2007-OTHERS.pdf

2125-KOLNP-2007-PETITION UNDER RULE 137.pdf

2125-KOLNP-2007-REPLY TO EXAMINATION REPORT.1.2.pdf

2125-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

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Patent Number

250425

Indian Patent Application Number

2125/KOLNP/2007

PG Journal Number

01/2012

Publication Date

06-Jan-2012

Grant Date

03-Jan-2012

Date of Filing

11-Jun-2007

Name of Patentee

RICHTER GEDEON VEGYESZETI GYAR RT

Applicant Address

GYOMROI UT 19-21, H-1103 BUDAPEST

Inventors:

#	Inventor's Name	Inventor's Address
1	HAASZ, FERENC	POLTENBERG UT. 55/B, H-2500, ESZTERGOM
2	VASS, ANDRAS	ADY ENDRE U. 65., H-8200, VESZPREM
3	BORBELY, LASZLO	KOSSUTH U. 5., H-2510, DOROG
4	JEKKEL, PETER	KINIZSI U. 2/A, H-2509, ESZTERGOM-KERTVAROS
5	DUDAS, JOZSEF	SOLYI U. 18, H-8200, VESZPREM

PCT International Classification Number

C07C 37/50

PCT International Application Number

PCT/HU2005/000128

PCT International Filing date

2005-12-07

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P0501044	2005-11-11	Hungary
2	P0402530	2004-12-08	Hungary