EP 0 693 475 A1
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` __________ ___________________
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`(19)
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` (11) EP 0 693 475 A1
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`(12) European Patent Application
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`(43) Publication date: (51) Int. Cl.6: C02C 217/72, C07C 215/54,
` 01/24/1996 Patent Gazette 1996/04 C07/C 215/62, C07C 215/30,
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` C07/C 217/74, C07C 219/22,
`(21) Application number: 95110864.6 C07/C 217/58, C07C 323/32,
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` C07/D 319/18, C07D 307/79,
`(22) Application date: 07/12/1995
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` A 61K 31/135
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`_____________________________________________________________________________
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`(84) Designated States: (72) Inventor:
` AT BE CH DE DK ES FR GB GR IE IT  Buschmann, Helmut, Dr.
` LI LU MC NL PT SE D-52066 Aachen (DE)
`  Strassburger, Wolfgang, Prof. Dr.
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`(30) Priority: 07/23/1994 DE 4426245 D-52146 Würselen, (DE)
`  Friderichs, Elmar, Dr.
`(71) Applicant: Grünenthal GmbH D-52223 Stolberg (DE)
` D-52078 Aachen (DE)
`_____________________________________________________________________________
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`(54) 1-Phenyl-3-dimethylaminopropane compounds having pharmacological effect
`(57) l-phenyl-3-dimethylaminopropane compounds are disclosed, also a preparation method
`thereof, and the use of these substances as pharmaceutical active ingredients.
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` Printed by Rank Xerox (UK) Business Services
` 2.9.7/3.4
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`EP 0 693 475 A1
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`RS 1006 - 000001
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`EP 0 693 475 A1
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`Description
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` The present invention relates to l-phenyl-3-dimethylaminopropane compounds, to a method of prepar-
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`ing them, and to the use of these substances as pharmaceutical active ingredients.
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` The treatment of chronic and non-chronic pain situations is of great importance in medicine. This is
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`reflected in the large number of publications. Thus, for example, 1-naphthyl-3-aminopropane-1-ols with
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`an analgesic-narcotic effect are known from EP 176 049. Secondary and tertiary alcohols with γ-amino
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`groups are described in J. Pharm. Sci. 59, 1038 (1970) and in J. Prakt. Chem. 323, 793 (1981). Phenyl-
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`dimethylaminopropanols containing a para-substituted phenyl radical are described in Chem. Abstr. 54,
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`20963c (1960) and in Chem. Abstr. 63, 6912e (1965). These compounds also possess analgesic properties.
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`In contrast, the 3-dimethylaminopropan-1-ols containing 2-phenyl radicals described in DE 32 42 922 have
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`an antidepressant effect. The 1-phenyl-propan-1-ols described in J. Pharm. Sci. 57, 1487 (1968) have
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`different pharmacological effects depending on the γ-aza ring.
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` Opioids have been used for many years as analgesics for the treatment of pain, although they give rise
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`to a series of side effects, for example addiction and dependency, respiratory depression, gastrointestinal
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`inhibition and obstipation. They can therefore only be given over an extended period of time or in higher
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`doses subject to special precautionary measures such as special prescription regulations (Goodman,
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`Gilman in "The Pharmacological Basis of Therapeutics", Pergamon Press, New York (1990)).
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` Tramadol hydrochloride - (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
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`hydrochloride - assumes a special position amongst centrally-acting analgesics, since this active
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`ingredient gives rise to a pronounced inhibition of pain without the side effects which are known for
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`opioids (J. Pharmacol. Exptl. Ther. 267, 331 (1993)). Tramadol is a racemate and consists of identical
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`amounts of (+) and (-) enantiomer. In vivo the active ingredient forms the metabolite O-desmethyl-
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`tramadol, which is likewise present as a mixture of enantiomers. Investigations have shown that both the
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`enantiomers of tramadol and the enantiomers of tramadol metabolites contribute to the analgesic effect (J.
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`Pharmacol. Exp. Ther. 260, 275 (1992)).
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` The underlying object of the present invention was to provide substances with an analgesic effect, which
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`are suitable for the treatment of severe pain without giving rise to the side effects which are typical of
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`opioids. A further object was to provide analgesic substances which do not exhibit the side effects, for
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`example nausea and vomiting, which occur during treatment with tramadol in some cases.
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` It has been found that these stringent requirements are met by certain 1-phenyl-
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`dimethylaminopropane compounds. These substances are characterized by a pronounced analgesic
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`effect which is significantly enhanced compared with that of tramadol. The present invention
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`accordingly relates to l-phenyl-3- dimethylaminopropane compounds of formula I
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`EP 0 693 475 A1
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`in which
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` denotes OH, F, Cl, H or an OCOR6 group in which R6 is a C1-3 -alkyl group;
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` X
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`R1 is a C1-4 -alkyl group, R2 denotes H or a C1-4-alkyl group and R3 denotes H or a straight chain C1-4 -
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`alkyl group, or R2 and R3 together constitute a C4-7-cycloalkyl radical, and if R5 is H, R4 denotes meta-O-
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`Z, where Z is H, C1-3-alkyl, PO(OC1-4-alkyl)2, CO(OC1-5-alkyl), CONH-C6 H4-(C1-3-alkyl) or CO-C6H 4 -
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`R7, wherein R7 is ortho-OCOC1-3-alkyl or meta- or para-CH2 N(R6)2, where R6 is C1-4-alkyl or 4-
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`morpholino, or R4 denotes meta-S-C1-3-alkyl, meta-Cl, meta-F or meta-CR9 R10R11, where R9, R10, R11 are
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`H or F, ortho-OH, ortho-O-C2-3-alkyl, para-F or para-CR9 R10R11, or
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`or
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`if R5denotes Cl, F, OH or O-C1-3-alkyl in the para-position, R4 denotes Cl, F, OH or O-C1-3-alkyl in the
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`meta-position, or R4 and R5 together represent 3,4-OCH=CH- or 3,4-OCH=CHO--, as diastereoisomers or
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`enantiomers in the form of free bases or salts of physiologically acceptable acids.
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`EP 0 693 475 A1
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`1-phenyl-3-dimethylaminopropane compounds of formula I are preferred in which X constitutes OH, F,
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`Cl or H; R1 is an C1-4-alkyl group; R2 is H or CH3, and R3 is H or CH3, and if R5 is H, R4 denotes -OC1-3-
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`alkyl, -OH, -S-C1-3-alkyl, F, Cl, CH3, -CF2H or –CF3 in the meta-position, or para-CF3, or if R5 is a para-
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`Cl or para-F, R4 represents meta-Cl or meta-F, or R4 and R5 together represent 3,4-OCH=CH-.
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`1-phenyl-3-dimethylaminopropane compounds of formula I are particularly preferred in which the R2 and
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`R3 radicals are different, in the form of their diastereoisomers of configuration Ia
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`The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane
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`compounds of formula I, in which the variable X represents OH, which is characterized in that a β-
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`dimethylaminoketone of formula II
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`is reacted with an organometallic compound of formula III
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`in which Z denotes MgCl, MgBr, MgI or Li, to form a compound of formula I with X = OH.
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` The reaction of a β-dimethylaminoketone with a Grignard reagent of formula III, in which Z denotes
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`MgCl, MgBr or MgI, or with an organolithium compound of formula III, can be carried out in an a
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`aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures between -70° C and
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`+60° C. Organolithium compounds of formula III can be obtained by the replacement of halogen by
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`lithium, for example, by reacting a compound of formula III, in which Z represents Cl, Br or I, with for
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`example a solution of n-butyllithium in n-hexane.
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`β-dimethylaminoketones of formula II can be obtained from ketones of general formula IV
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`by reaction with dimethylamine hydrochloride and formaldehyde in glacial acetic acid or in a C1-4-alkyl
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`alcohol or by reaction with dimethylammonium ethylene chloride in acetonitrile using acetyl chloride as a
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`catalyst (Synthesis 1973, 703).
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` Upon reaction of a β-dimethylaminoketone of formula II, in which the variables R2 and R3 are
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`different, with an organometallic compound of formula III, 1-phenyl-3-dimethylaminopropane
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`compounds of formula I are obtained having the relative configuration of formula Ia
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`in which the X and the dimethylamino group are disposed threo in relation to each other. In contrast, if
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`the reaction for the preparation of 1-phenyl-1-hydroxy-3-aminopropanes were carried out according to the
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`method disclosed in DD 124 521, i.e. if β-aminoketones of formula V
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`EP 0 693 475 A1
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`were reacted with an alkyl Grignard reagent R 1MgHal, this would result in compounds with the
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`relative configuration lb
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`in which the OH group and the dimethylamino radical are disposed erythro in relation to each other.
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` 1-phenyl-3-dimethylaminopropane compounds of formula I, in which R4 and/or R5 constitute the OH
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`group, can be prepared from the corresponding 1-(4(5)-methoxyphenyl)-3-dimethylaminopropanol
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`compounds by selective ether cleavage with diisobutylaluminium hydride in an aromatic hydrocarbon, for
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`example toluene, at a temperature between 60 and 130° C (Synthesis 1975, 617).
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` The present invention also relates to a method of preparing l-phenyl-3-dimethylaminopropane
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`compounds of formula I, in which X is H, which is characterized in that a compound of formula I,
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`in which X is Cl, is reacted with zinc borohydride, zinc cyanoborohydride and/or tin
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`cyanoborohydride.
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` The reaction is usually conducted in a solvent, for example diethyl ether and/or tetrahydrofuran, at a
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`temperature between 0° C and 30° C.
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` Compounds of formula I, in which X is H and R4 and/or R5 constitute the OH group, can be prepared
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`from the corresponding methoxyphenyl compounds by heating them for several hours with concentrated
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`hydrobromic acid (Chem. Rev. 54, 615 (1954); J. Am. Chem. Soc. 74, 1316 (1952)).
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` The present invention further relates to a method of preparing 1-phenyl-3-dimethylaminopropane
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`compounds of formula I, where X is F, which is characterized in that a compound of formula I, in which
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`X is OH, is reacted with dimethylaminosulfur trifluoride in a solvent.
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` Suitable solvents include dichloromethane, 1,1,2-trichloroethane and/or toluene. The reaction is usually
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`conducted at a temperature between -50° C and +30° C (Org. React. 35, 513 (1988)). If a compound of
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`formula I with X = OH is used in which R4 and/or R5 constitute OH groups, these OH groups must be
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`protected before reaction with the fluorine compound, for example by reaction with benzoyl chloride.
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`The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane
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`compounds of formula I, in which X is Cl, which is characterized in that a compound of formula I, in
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`which X is OH, is reacted with thionyl chloride.
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`EP 0 693 475 A1
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` The reaction is usually conducted in the absence of solvent at a temperature between 0° C and 20° C.
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`Replacement of OH by C takes place with retention of the configuration.
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` The present invention also relates to a method of preparing 1-phenyl-3-dimethylaminopropane
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`compounds of formula I, in which X represents an OCOR6 group where R6 is a C1-3-alkyl, which is
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`characterized in that a compound of formula I, in which X represents OH, is reacted with an acid chloride
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`Cl-COOR6.
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` The reaction is preferably conducted in a solvent, for example dichloromethane, toluene and/or
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`tetrahydrofuran, at a temperature between -10° C and +30° C.
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` 1-phenyl-3-dimethylaminopropane compounds of formula I, in which R5 is H and R4 is a meta-
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`phosphate group, meta-carbonate group, meta-carbamate group or meta-carboxylate group, can be
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`obtained by the reaction of the corresponding 1-(3-hydroxyphenyl)-3-dimethylaminopropane compounds
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`of formula I in the form of their alkali salts with an alkali salt of a dialkyl chlorophosphate, with an alkyl
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`chloroformate, with an aryl isocyanate or with a carboxylic acid chloride. These reactions are usually
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`conducted in a solvent, for example toluene, dichloromethane, diethyl ether and/or tetrahydrofuran, at
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`temperatures between -15° C and +110° C (Drugs of the Future 16, 443 (1991); J. Med. Chem. 30, 2008
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`(1987) and 32, 2503 (1989); J. Org. Chem. 43, 4797 (1978); Tetrahedron Lett. 1977, 1571; J. Pharm. Sci.
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`57, 774 (1968)).
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` The compounds of formula I can be converted in a known manner into their salts with physiologically
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`acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid,
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`formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid,
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`citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent, for
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`example
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`EP 0 693 475 A1
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`diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover,
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`trimethylchlorosilane in aqueous solution is suitable for the preparation of hydrochlorides.
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` 1-phenyl-3-dimethylaminopropane compounds of formula I are toxicologically harmless, so that they
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`are suitable as pharmaceutical active ingredients in drugs.
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` Accordingly, the present invention also relates to the use of a 1-phenyl-3-dimethylaminopropane
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`compound of formula I as a pharmaceutical active ingredient.
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` Compounds of formula I are preferably used for the treatment of pain.
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` In addition to at least one 1-phenyl-3-dimethylaminopropane compound of formula I, the analgesics
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`according to the invention may contain carriers, fillers, solvents, diluents, colorants and/or binders. The
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`selection of auxiliary substances and of the amounts of the same to be used depends on whether the drug
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`is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally
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`or locally, for example for infections of the skin, of the mucous membranes or of the eye. Preparations in
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`the form of tablets, dragees, capsules, granules, drops, liquids and syrups are suitable for oral application.
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`Solutions, suspensions, readily reconstitutable dry preparations, and sprays are suitable for parenteral,
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`topical and inhalative applications. Compounds of formula I according to the invention in a deposit in
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`dissolved form or in a patch, optionally with the addition of a skin penetration promoter, are suitable
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`preparations for percutaneous application. Forms of preparations which can be administered orally or
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`percutaneously may effect delayed release of the compounds of formula I according to the invention.
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` The amount of active ingredient to be administered to patients varies depending on the patient's weight,
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`on the manner of administration, the indication and the degree of severity of the illness. 50 to 500 mg/kg
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`of at least one 1-phenyl-3-dimethylaminopropane compound of formula I are usually administered.
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`Examples
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` The yields of the compounds prepared have not been optimized.
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` All temperatures are uncorrected.
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` Unless otherwise indicated, petroleum ether with a boiling point of 50-70° C was used. The term
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`"ether" denotes diethyl ether.
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` Silica gel 60 (0.040-0.063 mm) manufactured by E. Merck, Darmstadt, was used as the stationary
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`phase for column chromatography.
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` Thin layer chromatography investigations were conducted using prefabricated silica gel 60 F 254
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`HPTLC plates manufactured by E. Merck, Darmstadt
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`Racemate separation was effected on a Chiracel OD column.
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` The mixture ratios of the mobile phases for all chromatographic investigations are expressed as
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`volume/volume.
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` RT denotes room temperature; m.p. denotes melting point.
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`Example 1
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`(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, hydrochloride (1)
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` 207.63 g (1.11 mole) 3-bromoanisole dissolved in 400 ml dry tetrahydrofuran were added drop-wise to
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`26.99 g (1.11 mole) magnesium turnings in 150 ml dry tetrahydrofuran so that the reaction mixture boiled
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`gently. After the addition of 3-bromoanisole was complete the mixture was heated under reflux for one
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`hour and thereafter was cooled to 5-10° C. 128.30 g (0.89 mole) 1-dimethylamino-2-methylpentan-3-one
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`dissolved in 400 ml tetrahydrofuran were added at this temperature.
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`The reaction mixture was allowed to stand overnight and then cooled again to 5 -10° C. The Grignard
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`solution was decomposed by the addition of 300 ml of 20% ammonium chloride solution. The reaction
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`mixture was diluted with 400 ml ether, the organic phase was separated off and the aqueous phase was
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`extracted twice with 250 ml ether. The combined organic phases were dried over sodium sulfate. After
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`removing the solvent by distillation, the residue (212 g) was taken up in 3200 ml 2-butanone and added to
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`120.60 g (1.11 mole) trimethylchlorosilane and 20 ml water. 121.5 g of hydrochloride (1) (38%
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`theoretical) with a melting point of 198 -199° C crystallized out at 4-5° C.
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`Example 2
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`Enantiomers of (1):
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`(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, hydrochloride (-1)
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`and
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`(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, hydrochloride (+1)
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` The base was released from (1) with dichloromethane/sodium hydroxide solution. After drying the
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`solution, dichloromethane was distilled off under vacuum. The racemate was then separated on the chiral
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`HPLC column. The hydrochlorides, which had a melting point of 150 -151° C, were prepared from the
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`enantiomers obtained by reaction with trimethylchlorosilane/water in 2-butanone.
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`(-1): yield: 42% theoretical
`RT = -31.8° (c = 0.99; methanol)
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`RT = +33.0° (c = 0.96; methanol)
`(+1): yield: 41% theoretical [α]D
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`Example 3
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`(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (2)
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` 39 g of crude mixture were prepared analogously to Example 1 from 15 g (105 mmol) 1-
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`dimethylamino-2-methylpentan-3-one, 35.5 g (157 mmol) 4-bromo-1,2-dichlorobenzene and 3.8 g (157
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`mmol) magnesium turnings. This mixture was introduced onto a 7 x 40 cm column packed with silica gel
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`and eluted with 4:1 ethyl acetate/methanol. 14.9 g of base were obtained, from which 11.2 g of
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`hydrochloride (2) (31% theoretical) with a melting point of 183 -184° C were obtained with
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`trimethylchlorosilane/water in 2-butanone/diisopropyl ether.
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`Example 4
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`(2RS,3RS)-3-(3-isopropoxyphenyl)-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (3)
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` 25 g of crude mixture were prepared analogously to Example 1 from 14.3 g (100 mmol) 1-
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`dimethylamino-2-methylpentan-3-one, 20.0 g (157 mmol) 1-bromo-3-isopropoxybenzene and 2.79 g (115
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`mmol) magnesium turnings. This mixture was introduced on to a 7 x 40 cm column packed with silica gel
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`and eluted with 15:1 ethyl acetate/methanol. 9.0 g of base were obtained, from which 8.3 g of
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`hydrochloride (3) (26% theoretical) with a melting point of 133 -134° C were obtained with
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`trimethylchlorosilane/water in 2-butanone.
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`Example 5
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`(2RS,3RS)-3-(3-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (4)
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`63 g of crude mixture were obtained under the conditions cited for Example 1 from 38.0 g (270 mmol) 1-
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`dimethylamino-2-methylpentan-3-one, 74.7 g (390 mmol) 1-bromo-3-chlorobenzene and 9.50 g (390
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`mmol) magnesium turnings. This mixture was introduced onto a 7 x 45 cm column packed with silica gel
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`and eluted with 7:1 diisopropyl ether/methanol. 12.8 g of base were obtained, from which 10.8 g of
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`hydrochloride (4) (14% theoretical) with a melting point of 160 -162° C were obtained with
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`trimethylchlorosilane/water in 2-butanone/ether.
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`Example 6
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`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-trifluoromethylphenyl)-pentan-3-ol, hydrochloride (5)
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` 21.2 g of crude mixture were obtained under the conditions cited for Example 1 from 14.3 g (100
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`mmol) 1-dimethylamino-2-methylpentan-3-one, 29.3 g (130 mmol) 1-bromo-3-trifluoromethylbenzene
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`and 3.2 g (130 mmol) magnesium turnings. This mixture was introduced onto a 6 x 40 cm column packed
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`with silica gel and eluted with 10:1 diisopropyl ether/methanol. 9.1 g of base were obtained, from which
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`7.8 g of hydrochloride (5) (18.5% theoretical) with a melting point of 189 -190° C was obtained with
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`trimethylchlorosilane/water in 2-butanone.
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`Example 7
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`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)-pentan-3-ol, hydrochloride (6)
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`75 g of crude mixture were obtained as in Example 1 from 47.3 g (330 mmol) 1-dimethylamino-2-
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`methylpentan-3-one, 64.6 g (400 mmol) 3-bromotoluene and 9.72 g (400 mmol) of magnesium turnings.
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`This mixture was introduced onto a 7 x 50 cm column packed with silica gel and eluted with 7:1
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`diisopropyl ether/methanol. 24.3 g of base were obtained, from which 21.5 g of hydrochloride (6) (24%
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`theoretical) with a melting point of 154 -155° C were obtained with trimethylchlorosilane/water in 2-
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`butanone.
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`Example 8
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`(2RS, 3RS)-1-dimethylamino-3-(3-fluorophenyl)-2-methylpentan-3-ol, hydrochloride (7)
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`70 g of crude mixture were obtained under the conditions cited for Example 1 from 54.0 g (380 mmol) 1-
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`dimethylamino-2-methylpentan-3-one, 82.5 g (470 mmol) 1-bromo-3-fluorobenzene and 9.23 g (470
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`mmol) magnesium turnings. This mixture was introduced onto a 7 x 50 cm column packed with silica gel
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`and eluted with 1:1 ethyl acetate/methanol. 13.0 g of base were obtained, from which 11.2 g of
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`hydrochloride (7) (11.5% theoretical) with a melting point of 145 -146° C was obtained with
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`trimethylchlorosilane/water in 2-butanone.
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`Example 9
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`(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (8)
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`7.0 g (34 mmol) 1-bromo-3-difluoromethylbenzene, prepared from 3-bromobenzaldehyde and
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`diethylaminosulphur trifluoride in dichloromethane according to Org. React. 35, 513 (1988) were
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`dissolved in 110 ml of dry tetrahydrofuran and cooled to -75° C. After the addition of 21.12 ml (34
`
`mmol) of a 1.6 molar solution of n-butyllithium in hexane the mixture was stirred for one hour at -75° C.
`
`4.8 g (34 mmol) 1-dimethylamino-2-methylpentan-3-one dissolved in 15 ml of dry tetrahydrofuran were
`
`then added dropwise. The reaction mixture was warmed to room temperature over 2.5 hours.
`
` Work-up was effected by the drop-wise addition of 65 ml of 5% hydrochloric acid with cooling in an
`
`ice bath, so that the internal temperature did not exceed 15° C. After phase separation the organic phase
`
`was extracted with 40 ml of 5% hydrochloric acid. The combined aqueous phases were washed twice
`
`with 50 ml ether. In order to release the base, the mixture was added to concentrated sodium hydroxide
`
`solution and extracted with dichloromethane. 7.8 g of crude product were obtained in this manner and
`
`was introduced on to a 7 x 40 cm column packed with silica gel. Elution with 1:1 ethyl acetate/methanol
`
`gave 4.89 g of base, from which 4.6 g of hydrochloride (8) (44% theoretical) with a melting point of 194-
`
`195° C was obtained with trimethylchlorosilane/water in 2-butanone.
`
`
`Example 10
`
`
` (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulphanylphenyl)-pentan-3-ol, hydrochloride (9)
`
`
`
` 38 g of crude mixture were obtained under the conditions cited for Example 1 from 17.6 g (123 mmol)
`
`RS 1006 - 000015
`
`

`
`EP 0 693 475 A1
`
`
`1-dimethylamino-2-methylpentan-3-one, 25.0 g (123 mmol) 1-bromo-3-methylsulphanylbenzene and 3.0
`
`g (123 mmol) magnesium turnings. This mixture was introduced on to a 7 x 40 cm column packed with
`
`silica gel and eluted with 10:1 ethyl acetate/methanol. 8.35 g of base were obtained, from which 7.2 g of
`
`hydrochloride (9) (19% theoretical) with a melting point of 159 -160° C were obtained with
`
`trimethylchlorosilane/water in 2-butanone.
`
`11
`
`
`
`RS 1006 - 000016
`
`

`
`Example 11
`
`EP 0 693 475 A1
`
`
`
`
`
`
`(2RS,3RS)-3-benzofuran-6-yl-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (10)
`
`
`
` 3.45 g (18 mmole) 6-bromobenzofurane (prepared according to EP 355 827) and 6 ml 1,2-
`
`dibromoethane, dissolved in 60 ml dry ether, were added drop-wise over 1.5 hours to 2.12 g (87 mmol)
`
`magnesium turnings in 30 ml dry ether; after the addition the mixture was heated under reflux for 30
`
`minutes. Thereafter, 2.5 g (18 mmol) 1-dimethylamino-2-methylpentan-3-one dissolved in 7.5 ml ether
`
`was added drop-wise over 1.5 hours while cooling in an ice bath to maintain an internal temperature of 5 -
`
`10° C. The reaction mixture was allowed to stand for 12 hours at room temperature, and was then cooled
`
`again to 5-10° C and added to 35 ml of 20% aqueous ammonium chloride solution. After phase
`
`separation, the aqueous phase was extracted twice with 50 ml ether. The combined organic phases were
`
`dried over sodium sulfate. After removing the solvent by distillation, the residue (3.9 g) was introduced
`
`onto a 5 x 16 cm column packed with silica gel. 0.95 g of base were obtained by elution with 7:1
`
`diisopropyl ether/methanol, from which 0.82 g of hydrochloride (10) (15.5% theoretical) with a melting
`
`point of 162° were obtained with trimethylchlorosilane/water in ethyl acetate/2-butanone.
`
`
`Example 12
`
`
`
`
`(2RS,3RS)-1-dimethylamino-2-methyl-3-(4-trifluoromethylphenyl)-pentan-3-ol, hydrochloride (11)
`
` 44 g of crude mixture were obtained as in Example 1 from 20 g (140 mmol) 1-dimethylamino-2-
`
`RS 1006 - 000017
`
`

`
`EP 0 693 475 A1
`
`
`methylpentan-3-one, 31.5 g (140 mmol) 1-bromo-4-trifluoromethylbenzene, 16.5 g (680 mmol)
`
`magnesium turnings and 47 ml 1,2-dibromoethane. This mixture was introduced onto a 7 x 50 cm
`
`column packed with silica gel and eluted with 5:1 ethyl acetate/methanol. 16.4 g of base were obtained,
`
`from which 12.3 g of hydrochloride (11) (27% theoretical) with a melting point of 170-171° C were
`
`obtained with trimethylchlorosilane/water in 2-butanone.
`
`12
`
`
`
`
`
`RS 1006 - 000018
`
`

`
`EP 0 693 475 A1
`
`
`Example 13
`
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-hexan-3-ol, hydrochloride (12)
`
`
`
` 18.5 g of crude mixture were obtained as in Example 1 from 10 g (70 mmol) 1-dimethylamino-hexan-
`
`3-one, 18.7 g (100 mmol) 1-bromo-3-methoxybenzene and 2.3 g (100 mmol) magnesium turnings. This
`
`mixture was introduced onto a 6 x 50 cm column packed with silica gel and eluted with 1:1 ethyl
`
`acetate/methanol. 6.84 g of base were obtained, from which 6.15 g of hydrochloride (12) (32%
`
`theoretical) with a melting point of 179-180° C were obtained with trimethylchlorosilane/water in 2-
`
`butanone.
`
`
`Example 14
`
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-heptan-3-ol, hydrochloride (13)
`
` 17.3 g of crude mixture were obtained as in Example 1 from 10 g (64 mmol) 1-dimethylamino-heptan-
`
`3-one, 15.9 g (157 mmol) 1-bromo-3-methoxybenzene and 2.06 g (85 mmol) magnesium turnings. This
`
`mixture was introduced onto a 6 x 40 cm column packed with silica gel and eluted with ethyl acetate. 5.4
`
`g of base were obtained, from which 4.1 g of hydrochloride (13) (21% theoretical) with a melting point of
`
`150° C were obtained with trimethylchlorosilane/water in 2-butanone.
`
`
`Example 15
`
`(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol, hydrochloride (14)
`
`
`
` 37 g of crude mixture were obtained as in Example 1 from 18.6 g (118 mmol) 1-dimethylamino-4,4-
`
`dimethylpentan-3-one, 28.4 g (152 mmol) 1-bromo-3-methoxybenzene and 3.7 g (152 mmol) magnesium
`
`turnings. This mixture was introduced onto a 7 x 40 cm column packed with silica gel and eluted with
`
`5:1 ethyl acetate/methanol. 2.2 g of base were obtained, from which 1.8 g of hydrochloride (14) (5%
`
`theoretical) with a melting point of 213° C. were obtained with trimethylchlorosilane/water in 2-
`
`butanone.
`
`Example 16
`
`
` (2RS,3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol, hydrochloride (15)
`
`
`RS 1006 - 000019
`
`

`
`EP 0 693 475 A1
`
`
` 21 g of crude mixture were obtained as in Example 1 from 5.3 g (41 mmol) 4-dimethylamino-3-
`
`methylbutan-3-one, 23.0 g (123 mmol) 1-bromo-3-methoxybenzene and 3.0 g (123 mmol) magnesium
`
`turnings. This mixture was introduced onto a 4.5 x 27 cm column packed with silica gel and eluted with
`
`4:1 ethyl acetate/methanol. 4.0 g of base were obtained, from which 3.6 g of hydrochloride (15) (32%
`
`theoretical) with a melting point of 124° C. were obtained with trimethylchlorosilane/water in 2-
`
`butanone.
`
`
`
`
`
`13
`
`RS 1006 - 000020
`
`

`
`Example 17
`
`EP 0 693 475 A1
`
`
`
`
`
`
`
`
`
`
`Enantiomers of (15):
`
`(-)-(2S,3S)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol, hydrochloride (-15)
`
`and
`
`(+)-(2R,3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol, hydrochloride (+15)
`
`
`The base was released from hydrochloride (15), which was prepared as in Example 16, with
`
`dichloromethane/sodium hydroxide solution. After drying and removal of dichloromethane by distillation,
`
`the racemate was then separated into the enantiomers on a chiral HPLC column. The hydrochlorides were
`
`obtained from the enantiomers with trimethylchlorosilane/water in 2-butanone.
`
`(-15): yield: 41% theoretical
`
`m.p.: 117-118° C
`RT = -38.6° (c=1.05; methanol)
`[α]D
`
`
`
`
`(+15): yield: 41% theoretical
`
`m.p.: 118-119° C
`RT = +41.0° (c=1.01; methanol)
`
`[α]D
`
`Example 18
`
`
`
`(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol, hydrochloride (16)
`
`The base was released from compound (1), which was prepared as in Example 1, with
`
`
`
`dichloromethane/sodium hydroxide solution. After drying the solution, dichloromethane was removed by
`
`RS 1006 - 000021
`
`

`
`EP 0 693 475 A1
`
`
`distillation. 4.3 g (17 mmol) of base were dissolved in 25 ml dry toluene and slowly added drop-wise to
`
`71 ml (85mmol) of a 1.2 molar solution of diisobutylaluminium hydride in toluene.
`
`
`
`
`
`14
`
`RS 1006 - 000022
`
`

`
`EP 0 693 475 A1
`
`
`When the addition was complete, the mixture was heated for 8 hours under reflux and then cooled to
`
`room temperature. The reaction mixture was diluted with 25 ml toluene. 9.4 ml ethanol followed by 9.4
`
`ml water were added drop-wise while cooling in an ice bath. After stirring for one hour while cooling in
`
`the ice bath, the reaction mixture was freed from aluminum salts by filtration, and the residue was washed
`
`three times with 50 ml toluene in each case. Thereafter the combined organic phases were dried and
`
`toluene was removed by distillation. 3.95 g of hydrochloride (16) (85% theoretical) with a melting point
`
`of 213 -214° C were obtained from the base with aqueous hydrochloric acid solution in acetone.
`
`
`Example 19
`
`
`
`
`
`
`
`Enantiomers of (16):
`
`(-) (2S, 3S)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol, hydrochloride (-16)
`
`and
`
`(+)(2S,3S)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol hydrochloride (+16)
`
`The enantiomers (-16) and (+16) were prepared under the conditions cited in Example 2.
`
` yield: 85% theoretical
`(-16):
` m.p.: 208-209° C
`
`RT = -34.6° (c=0.98; methanol)
`[α]D
`
`(+16): yield: 85% theoretical
`
`m.p.: 206-207° C
`RT = +34.4° (c=1.06; methanol)
`
`[α]D
`
`15
`
`
`
`
`
`
`
`RS 1006 - 000023
`
`

`
`EP 0 693 475 A1
`
`
`Example 20
`
`
`
`(1RS,2RS)-3-(3dimethylamino-1-hydroxy-1,2-dimethylpropylphenol, hydrochloride (17)
`
`
`
`
`
` Compound (17) was prepared under the conditions cited in Example 18 starting from methoxy
`
`compound (15) which was obtained as in Example 16.
`
`Yield: 85% theoretical
`
`m.p.: 232° C
`
`
`Example 21
`