WO1996014283A1 - Process and intermediates for preparing triphenyltrifluoropropanes and -propenes - Google Patents

Process and intermediates for preparing triphenyltrifluoropropanes and -propenes Download PDF

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WO1996014283A1
WO1996014283A1 PCT/HU1995/000056 HU9500056W WO9614283A1 WO 1996014283 A1 WO1996014283 A1 WO 1996014283A1 HU 9500056 W HU9500056 W HU 9500056W WO 9614283 A1 WO9614283 A1 WO 9614283A1
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formula
group
hydroxy
hydrogen
stands
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PCT/HU1995/000056
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French (fr)
Inventor
Gábor NÉMETH
Gyula Simig
Dániel BÓZSING
Györgyi KOVÁNYI
Éva RÁKÓCZY
Ildikó RÁTZ
Gábor BLASKÓ
László LADÁNYI
János EGRI
Erzsébet KISS
János IMRE
Györgyi VERECZKEY
Kálmán NAGY
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EGIS Gyógyszergyár Rt.
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Priority claimed from HU9403142A external-priority patent/HUT72892A/en
Priority claimed from HU9403143A external-priority patent/HUT72891A/en
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to AU38790/95A priority Critical patent/AU3879095A/en
Publication of WO1996014283A1 publication Critical patent/WO1996014283A1/en

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    • C07—ORGANIC CHEMISTRY
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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    • C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
    • C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
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    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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    • C07C43/00—Ethers; Compounds having groups, groups or groups
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
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    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

Definitions

  • the invention refers to a novel process for preparing triphenyltrifluoropropanes and -propenes of the formula
  • R- j represents hydrogen
  • R 2 stands for hydroxy
  • R-l forms together with R 2 a valence bond
  • B is hydrogen, methyl, methoxy methyl, tetrahydro- pyranyl or a group of the formula
  • R3 represents a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula R -O-CH 2 -CH 2 -N-R 4 b
  • R4 stands for hydrogen or benzyl.
  • the invention refers to novel triphenyltrifluoropropanes and -propenes being a sub-group of the compounds of the formula III as well as to novel 2- -phenyl-3,3,3-trifluoropropiophenone derivatives that are useful intermediates in the synthesis of the compounds of the formula III.
  • triphenyltrifluoropropene derivatives having antitumor activity are known.
  • the compound having the most favourable activity is (E)-1 ,2- -diphenyl-3,3,3-trifluoro-1- ⁇ 4-[2-(2-hydroxyethylamino)- ethoxy]phenyl ⁇ -propene of the formula
  • Panomifen is suitable for the treatment of mammary tumor.
  • the known compounds are prepared from 1 ,2-diphenyl-3,3,3-trifluoropropane by means of a synthesis consisting of five or even more reaction steps. In many cases, the total yield of the known synthesis is less than 8 per cent.
  • a further drawback of the known synthesis resides in the fact that during the preparation of the starting 1 ,2 diphenyl-3,3,3-trifluoropropane, triphenyl- phosphine oxide is formed in stoichiometric amount. This by-product cannot be utilized, thus, it is a pollution source.
  • the aim of the invention is to provide an economical process that can be easily performed to yield the compounds of the formula III, especially panomifen.
  • Rg is a halo or benzyloxy
  • Rg is a halo or benzyloxy
  • a compound of the formula II obtained is transformed into another compound of the formula II within the definition of B given in relation to formula III in a manner known per se. and/or a compound of the formula II is dehydrated with an acid to obtain a propene derivative of the formula
  • B is as defined in relation to formula III, and, if desired, the compound of the formula I is transformed into another compound of the formula I within the definition of B in a manner known per se.
  • a sub-group of the compounds of the formula III consists of the hydroxypropane derivatives of the formula
  • the compounds of the formula II contain two chiral (i.e. asymmetrical) carbon atoms, consequently the compounds can exist in the form of optically active isomers, too.
  • the invention includes the optical isomers and any possible mixtures thereof such as the racemates.
  • compounds of the formula I may exist in the form of geometrical isomers.
  • the invention includes the geometrical isomers and any possible mixtures thereof.
  • compounds of the formula III include any possible optical isomers or geometrical isomers or any mixtures thereof.
  • the invention also refers to novel triphenyltrifluoro ⁇ propanes and -propenes of the formula III wherein R- j is hydrogen, R 2 represents hydroxy, and
  • B stands for hydrogen, methyl, methoxy methyl, tetra ⁇ hydropyranyl or a group of the formula a wherein R3 is a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula b_ wherein R 4 represents hydrogen or benzyl, or R-l forms together with R a valence bond, and B stands for tetrahydropyranyl or a group of the formula a wherein R3 is hydroxy, benzyloxy, methoxy- methoxy, tetrahydropyranyloxy or a group of the formula _ wherein R 4 is benzyl.
  • a preferred sub-group of the novel compounds of the formula III consists of the hydroxypropane derivatives of the formula II wherein,
  • a further preferred sub-group of the novel compounds of the formula III consists of propene derivatives of the formula I wherein
  • B stands for tetrahydropyranyl or a group of the formula a wherein R3 represents hydroxy, benzyloxy, methoxymethoxy or tetrahydropyranyloxy.
  • a halo means a fluoro, chloro, bromo or iodo.
  • halo is chloro.
  • the starting compound is a propiophenone derivative of the formula V wherein A represents hydrogen, and this compound is reacted with a bromobenzene of the formula VI wherein B stands for methyl, methoxymethyl, tetrahydropyranyl or a group of the formula a wherein R3 represents a halo, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula b wherein R 4 denotes benzyl.
  • the reagents are reacted under the conditions of the Grignard's reaction.
  • the expression "reacted under the conditions of the Grignard's reaction” refers to the following process: a bromobenzene of the formula VI is reacted with magnesium, preferably magnesium cuttings, to obtain a Grignard's reagent that is reacted with a propiophenone derivative of the formula V, and the reaction product is h ⁇ drolized in aqueous medium.
  • the Grignard's reaction is performed in any of the usual solvents such as diethyl ether, anisole, tetrahydro ⁇ furan etc.
  • the preferred solvent is tetrahydrofuran.
  • the Grignard's reagent is prepared preferably at the boiling point of the solvent employed. If necessary, the reaction of the bromobenzene derivative of the formula VI with the magnesium can be induced by the addition of an initiating reagent commonly used for this purpose such as bromine, carbon tetrachloride, magnesium bromide etc., or the magnesium cuttings are heated with some iodine.
  • the propiophenone derivative of the formula V is added preferably under cooling or at room temperature.
  • 2 to 5 moles of the Grignard's reagent are reacted with each mole of the propiophenone derivative.
  • the Grignard's reagent is employed in about twice excess.
  • the Grignard's reaction at an indifferent gas atmosphere, for example nitrogen stream.
  • the product obtained by the reaction of the Grignard's reagent with the propiophenone derivative of the formula V is hydrolized in an aqueous medium.
  • the reaction product can be poured onto an aqueous hydrochloric acid or ammonium chloride solution.
  • the hydroxypropane of the formula II formed is extracted with an organic solvent immiscible with water.
  • process a) of the invention results in hydroxy ⁇ propane derivatives of the formula II wherein B represents methyl, methoxymethyl, tetrahydropyranyl or a group of the formula a wherein R denotes benzyloxy, methoxy ⁇ methoxy, tetrahydropyranyl or a group of the formula b_ wherein R 4 is benzyl.
  • the starting compound is a propiophenone derivative of the formula V wherein A represents methoxy, methoxymethoxy, or a group of the formula __ wherein R5 stands for a halo, and this compound is reacted with bromobenzene under the conditions of the Grignard's reaction.
  • the Grignard's reaction is performed as described in accordance with process a).
  • hydroxypropane derivatives of the formula II are obtained wherein B denotes methyl, methoxymethyl or a group of the formula a wherein R3 stands for a halo.
  • a hydroxypropane derivative of the formula II obtained by process a) or b) is transformed into another compound of the formula II within the definition of B given in relation to formula III.
  • the transformation is performed by the conventional methods of the preparative organic chemistry.
  • a compound of the formula II wherein B denotes a group of the formula a wherein R3 stands for benzyloxy
  • R3 stands for benzyloxy
  • B can be catalytically hydrogenized to obtain a compound of the formula II wherein R3 is hydroxy
  • B stands for a group of the formula a wherein R3 represents a chloro
  • 2-aminoethanol to obtain a compound of the formula II wherein B repesents
  • the propene derivatives of the formula I are prepared from the hydroxypropane derivatives of the formula II wherein B is as defined in relation to formula III by dehydration with an acid treatment.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid etc. and organic acids such as oxalic acid or p-toluenesulfuric acid etc.
  • hydrochloric acid is employed.
  • the dehydration of the compounds of the formula II proceeds in a wide temperature range, however, a temperature between room temperature and 120 °C is used, in general.
  • the reaction can be performed in the presence or absence of a solvent. Aliphatic alcohols such as methanol or ethanol are preferred as solvent.
  • a propene derivative of the formula I is converted to another compound of the formula I within the definition of B given in relation to formula III by the usual methods of the preparative organic chemistry. Similar methods can be employed as at the transformations of the hydroxypropane derivatives of the formula II.
  • a compound of the formula I wherein B denotes a group of the formula a wherein R is hydroxy
  • R3 stands for chloro
  • a compound of the formula I wherein B represents a group of the formula a wherein R3 is benzyloxy can be hydrogenized in the presence of a suitable catalyst to obtain a corresponding compound of the formula I wherein R3 denotes hydroxy.
  • the Grignard's reaction employed according to the process of the invention is highly stereoselective.
  • the hydroxypropane derivative of the formula II formed consists of primarily an isomer pair of the configuration (1RS, 2RS), however, another isomer pair of the configuration (1RS, 2SR) is also present in minor quantities.
  • a diastereomeric mixture of the formula II is obtained that consists of mainly an isomer pair of the configuration (1 RS, 2SR).
  • the main product is separated, then dehydrated to obtain the corresponding propene derivative of the formula I.
  • Another possibility consists in the dehydration of the diastereomeric mixture.
  • the required isomer (E) is separated by conventional methods such as fractionated crystallization.
  • a third aspect of the invention refers to novel 2-phenyl-3,3,3-trifluoropropiophenone derivatives of the formula V wherein A represents hydrogen, hydroxy, methoxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula
  • the compounds of the formula V are prepared from the 2-phenyl-3,3,3-trifluoropropionic acid of the formula
  • the Friedel-Crafts' catalyst can be an inorganic salt of the type Lewis' acid e.g. aluminium trichloride, zinc chloride, boron trifluoride etc. or a mineral acid, especially sulfuric acid.
  • a mineral acid especially sulfuric acid.
  • anhydrous aluminium trichloride is employed as the catalyst.
  • the Friedel-Crafts' catalyst is generally used in stoichiometric amount or up to 30 per cent excess referring to the starting compound of the formula VII or a reactive derivative thereof.
  • the Friedel-Crafts' reaction is performed in a suitable organic solvent such as an aromatic hydrocarbon e.g. benzene; a halogenated hydrocarbon e.g. dichloroethane, trichloroethylene or tetrachloroethylene; nitrobenzene, nitromethane, carbon disulfide etc. or mixtures thereof. It is preferred to employ benzene or nitromethane as the organic solvent.
  • benzene or nitromethane as the organic solvent.
  • the Friedel-Crafts' reaction is performed at 0 to 50 °C, preferably at 10 to 15 °C.
  • a compound of the formula V wherein A represents hydroxy can be transformed into a compound of the formula V wherein A is a substituent other than hydrogen or hydroxy in a manner known per se. for example by alkylation, benzylation or reaction with dihydropyran.
  • Benzylization is performed with a benzyl halide, preferably benzyl chloride or bromide.
  • the above transformations of the compound of the formula V can be performed by using the conventional methods of the preparative organic chemistry (Greene, Protective Groups in Organic Synthesis, 1981 ).
  • the 2-phenyl-3,3,3-trifluroacetophenone derivatives of the formula V are prepared by reacting 2-phenyl-3,3,3-trifluoropropionic acid of the formula VII or a reactive derivative thereof, preferably 2-phenyl-3,3,3- -trifluoropropionyl chloride of the formula VIII in the presence of a Friedel-Crafts' catalyst with a benzene derivative of the formula IX wherein A is as stated in relation to formula V and, if desired, hydrolizing a compound of the formula V wherein A is other than hydrogen or hydroxy to obtain a compound of the formula
  • A denotes hydroxy with an acid, or alkylating a compound of the formula V wherein A stands for hydroxy to obtain a compound of the formula V wherein A represents methoxy, benzyloxy, methoxymethoxy or a group of the formula _.
  • R is as stated above with an alkylating agent, or reacting a compound of the formula
  • optically active compounds of the formula V can be prepared from the corresponding racemic compounds by conventional resolution methods. Various mixtures can be prepared from the optically active isomers.
  • the starting 2-phenyl-3,3,3-trifluoropropionic acid of the formula VII is a known compound /Dale et al., J. Org. Chem., 3 , 2543-2549 (1969)/.
  • the preferred reactive derivative thereof i.e. 2-phenyl-3,3,3-trifluoropropionyl chloride of the formula VIII is prepared from the carboxylic acid of the formula VII with an inorganic acid chloride such as thionyl chloride, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, suitably in the absence of a solvent.
  • the inorganic acid chloride is used in an equimolar amount or suitably in an excess.
  • the reaction is performed at a temperature between room temperature and the boiling point of the inorganic acid chloride used.
  • the excess of the inorganic acid chloride is distilled off and the remaining compound of the formula VIII is used in the Friedel-Crafts' reaction.
  • the benzene derivatives of the formula IX are commercially available or can be easily prepared by the usual methods of organic chemistry.
  • the bromobenzene derivatives of the formula VI used for the Grignard's reaction are partly known compounds /J. Am. Chem. Soc, 42, 163 (1920); EP No. 463 199; J. Steroid. Biochem., 23, 233-245 (1987); J. Chem. Soc, 69. 165 (1900)/ and some of them are commercially available.
  • the preparation of the novel compounds of the formula VI is shown in the description.
  • the process of the invention for the preparation of compounds of the formula III is highly economical.
  • Compounds of the formula V can be prepared with a yield of about 70 %.
  • the compounds of the formula II can be obtained by the Grignard's reaction with a yield of 75 % and they can be converted to the compounds of the formula I with a yield of 90 to 100 %.
  • reaction mixture is stirred for a further hour at this temperature, then poured onto 60 g of ice, and extracted 3 times with 50 cm 3 of chloroform each time.
  • the organic solutions are combined, washed with 15 cm 3 of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated.
  • the residual oil is crystallized from benzene to obtain 9.3 g (70 %) of the title compound.
  • the mixture is poured onto 80 g of crushed ice, extracted 3 times with 50 cm 3 of dichloromethane each time, the organic solutions are combined, washed twice with 40 cm 3 of water each time treated with active carbon, and evaporated.
  • the residual brown oil (1 1 .2 g) is transferred to a Kieselgel 60 column, and eluted with toluene. The solvent is evaporated, and the residual pale yellow oil is crystallized from kerosene at 10 °C to obtain 2.4 g (22 %) of the title compound.
  • the aqueous mixture is extracted 3 times with 30 cm 3 of chloroform each time, the combined organic phases are washed twice with 25 cm 3 of water each time, then dried over anhydrous magnesium sulfate, and evaporated.
  • the residue consists of about 3 g of greenish-yellow oil that is transferred to a column filled with Kieselgel 60.
  • the column is eluted with a mixture of kerosene and ethyl acetate (7:3) to obtain 1.3 g (40 %) of colourless oil that crystallizes on standing.
  • the crystalline product is treated with 10 cm 3 of kerosene, filtered, and washed with kerosene containing 5 per cent of isopropanol. In this way,
  • the reaction mixture is stirred for 15 minutes at this temperature, left to reach room temperature, stirred for further 6 hours at this temperature, then poured to 100 cm 3 of 10 per cent aqueous sodium carbonate solution at 10 to 15 °C, and the mixture is extracted 4 times with 50 cm 3 of chloro ⁇ form each time.
  • the organic layers are combined, washed twice with 90 cm 3 of 10 per cent aqueous sodium chloride solution each time, dried over anhydrous magnesium sulfate, filtered, and evaporated.
  • the residual yellow oil crystallizes on cooling.
  • the crystals are washed with kerosene to obtain 1.4 g (69.2 %) of the title compound as a white powder.
  • reaction mixture is stirred for one hour at 25 °C, then poured onto 100 cm 3 of 0.5 M aqueous hydrochloric acid cooled to 10 °C, and extracted twice with 50 cm 3 of dichloromethane each time. The organic layers are combined, washed with 50 cm 3 of water, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with toluene. The product is crystallized from isopropanol to obtain 1.12 g (40 %) of the title compound. M.p.: 85-87 °C.
  • Example 1 1 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1-(4- -methoxymethoxyphenyDpropane
  • furan is boiled under reflux for one hour to obtain the Grignard's reagent.
  • a solution of 1.32 g (5.0 mmoles) of 2-phenyl-3,3,3-tri- fluoropropiophenone in 5 cm 3 of anhydrous tetrahydro ⁇ furan is added while maintaining the temperature of the reaction mixture at 20 to 25 °C.
  • the mixture is stirred for one hour at 25 °C, then poured onto 80 cm 3 of 0.5 M aqueous ammonium chloride solution at 10 °C, and extracted twice with 40 cm 3 of dichloromethane each time. The organic layers are combined, washed with 40 cm 3 of water, and evaporated.
  • Example 12 1 RS,1 SR-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1-(4- -methoxymethoxyphenyDpropane
  • Example 13 1 RS,2SR-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -[4-(2- -chloroethoxy)phenyl]propane
  • reaction mixture is stirred for one hour at 25 °C, then poured onto 40 cm 3 of 0.5 M hydrochloric acid, and extracted three times using 20 cm 3 of dichloromethane each time.
  • the organic layers are combined, washed with 20 cm 3 of water, and evaporated.
  • the residual yellow oil is transferred to a column containing Kieselgel 60, and eluted with a mixture of toluene and ethyl acetate (95:5).
  • the product is recrystallized from isopropanol to obtain 1.00 g (75 %) of the title compound.
  • Example 15 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 - ⁇ 4-[2- -(methoxymethoxy)ethoxy]phenyl ⁇ propane
  • Example 20 1 ,2-diphenyl-3,3,3-trifluoro-1 -(4-(2-benzyloxyethoxy)- phenyljpropene
  • Example 21 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -[4-(2- -hydroxyethoxy)phenyl]propane
  • the crude product contains about 9 % of (Z) isomer.
  • (Z) isomer When recrystallized from 180 cm 3 of n-hexane, the content of (Z) isomer becomes lower than 2 %. 3.0 g (75 %) of the title compound are obtained. M.p.: 1 18-1 19 °C. Analysis for C 2 3H 1 9 F3 ⁇ 2 calculated: C 71.87 %, H 4.98 % F 14.83 %; found: C 71 ,91 %, H 4.94 % F 15.12 %.
  • Example 25 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -[N- -benzyl-N-(2-benzyloxyethyl)-4-(2-aminoethoxy)phenyl]- propane
  • Example 26 1 ,2-Diphenyl-3,3,3-trifl ⁇ oro-1-[N-benzyl-N-(2-benzyloxy- ethyl)-4-(2-aminoethoxy)phenyl]propene
  • the residual hydrochloride is treated with 5 per cent aqueous sodium hydrogen carbonate solution to obtain the free base that is extracted 3 times with 40 cm 3 of chloroform each time, the organic layers are combined, dried over anhydrous magnesium sulfate, and evaporated.
  • the q residue is treated with 20 cm° of n-hexane to obtain 0.68 g (64 %) of the title compound.
  • M.p. 96-98 °C (ethyl acetate).
  • M.p. in GB-P 2 058 061 is equivalent to 96-98 °C.
  • Example 29 1 ,2-Diphenyl-3,3,3-trifluoro-1- ⁇ 4-[2-(2-hydroxyethylamino)- -ethoxy]phenyl ⁇ propene

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Abstract

The invention refers to a process for preparing triphenyltrifluoropropanes and -propenes of formula III in which a 2-phenyl-3,3,3-trifluoropropiophenone derivative is reacted with bromobenzene under the conditions of the Grignard's reaction, and, if desired, a triphenyltrifluoropropane obtained is dehydrated to give a corresponding triphenyltrifluoropropane. The invention also refers to novel triphenyltrifluoropropanes and -propenes as well as novel 2-phenyl-3,3,3-trifluoropropiophenones used as intermediates.

Description

PROCESS AND INTERMEDIATES FOR PREPARING TRIPHENYLTRIFLUOROPROPANES AND -PROPENES
The invention refers to a novel process for preparing triphenyltrifluoropropanes and -propenes of the formula
Figure imgf000003_0001
wherein
R-j represents hydrogen, R2 stands for hydroxy, or R-l forms together with R2 a valence bond, B is hydrogen, methyl, methoxy methyl, tetrahydro- pyranyl or a group of the formula
- CHo - CH - 3 3
wherein R3 represents a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula R -O-CH2-CH2-N-R4 b
wherein R4 stands for hydrogen or benzyl.
Some of the compounds of the formula III have antitumor activity.
Furthermore, the invention refers to novel triphenyltrifluoropropanes and -propenes being a sub-group of the compounds of the formula III as well as to novel 2- -phenyl-3,3,3-trifluoropropiophenone derivatives that are useful intermediates in the synthesis of the compounds of the formula III.
From GB-P 2 058 061 , triphenyltrifluoropropene derivatives having antitumor activity are known. The compound having the most favourable activity is (E)-1 ,2- -diphenyl-3,3,3-trifluoro-1-{4-[2-(2-hydroxyethylamino)- ethoxy]phenyl}-propene of the formula
Figure imgf000004_0001
known under the international non-proprietory name panomifen, too Panomifen is suitable for the treatment of mammary tumor. The known compounds are prepared from 1 ,2-diphenyl-3,3,3-trifluoropropane by means of a synthesis consisting of five or even more reaction steps. In many cases, the total yield of the known synthesis is less than 8 per cent. A further drawback of the known synthesis resides in the fact that during the preparation of the starting 1 ,2 diphenyl-3,3,3-trifluoropropane, triphenyl- phosphine oxide is formed in stoichiometric amount. This by-product cannot be utilized, thus, it is a pollution source.
The aim of the invention is to provide an economical process that can be easily performed to yield the compounds of the formula III, especially panomifen.
It was found that the above aim is fulfilled by the novel process of the invention in which a) for the preparation of hydroxypropane derivatives of the formula
Figure imgf000005_0001
being a sub-group of the compounds of the formula III, wherein in formula II B stands for methyl, methoxy methyl, tetrahydropyranyl or a group of the formula _ wherein R3 represents a halo, benzyloxy, methoxymethoxy, tetra- hydropyranyloxy or a group of the formula b wherein R4 is benzyl, a propiophenone derivative of the formula
Figure imgf000006_0001
wherein A represents hydrogen, is reacted with a bromobenzene of the formula
Figure imgf000006_0002
wherein B is as stated above, under the conditions of the Grignard's reaction; or b) for the preparation of hydroxypropane derivatives of the formula II being a sub-group of the compounds of the formula III wherein in formula II B represents methyl, methoxymethyl or a group of the formula a wherein R3 stands for a halo, a propiophenone derivative of the formula V wherein A represents methoxy, methoxy- methoxy, tetrahydropyranyloxy or a group of the formula
O-CH2-CH2-R5 c
wherein Rg is a halo or benzyloxy, is reacted with bromo¬ benzene under the conditions of the Grignard's reaction; and, if desired, a compound of the formula II obtained is transformed into another compound of the formula II within the definition of B given in relation to formula III in a manner known per se. and/or a compound of the formula II is dehydrated with an acid to obtain a propene derivative of the formula
Figure imgf000007_0001
wherein B is as defined in relation to formula III, and, if desired, the compound of the formula I is transformed into another compound of the formula I within the definition of B in a manner known per se. A sub-group of the compounds of the formula III consists of the hydroxypropane derivatives of the formula
II wherein B is as stated in relation to formula III. These compounds are novel and are valuable intermediates for the preparation of known biologically active compounds, especially panomifen.
A further sub-group of the compounds of the formula
III consists of the propene derivatives of the formula I wherein B is as defined in relation to formula III. These compounds are partly novel. The novel compounds of the formula I are valuable intermediates for the preparation of known biologically active compounds, especially panomifen.
The compounds of the formula II contain two chiral (i.e. asymmetrical) carbon atoms, consequently the compounds can exist in the form of optically active isomers, too. The invention includes the optical isomers and any possible mixtures thereof such as the racemates.
Due to the double bond of the propene chain, compounds of the formula I may exist in the form of geometrical isomers. The invention includes the geometrical isomers and any possible mixtures thereof.
Thus, also compounds of the formula III include any possible optical isomers or geometrical isomers or any mixtures thereof.
The invention also refers to novel triphenyltrifluoro¬ propanes and -propenes of the formula III wherein R-j is hydrogen, R2 represents hydroxy, and
B stands for hydrogen, methyl, methoxy methyl, tetra¬ hydropyranyl or a group of the formula a wherein R3 is a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula b_ wherein R4 represents hydrogen or benzyl, or R-l forms together with R a valence bond, and B stands for tetrahydropyranyl or a group of the formula a wherein R3 is hydroxy, benzyloxy, methoxy- methoxy, tetrahydropyranyloxy or a group of the formula _ wherein R4 is benzyl. A preferred sub-group of the novel compounds of the formula III consists of the hydroxypropane derivatives of the formula II wherein,
B stands for hydrogen, methyl, ethoxymethyl, tetra¬ hydropyranyl or a group of the formula _, wherein R3 denotes a halo, hydroxy, benzyloxy, methoxv- methoxy, tetrahydropyranyloxy or a group of the formula t> wherein R4 is hydrogen or benzyl. A further preferred sub-group of the novel compounds of the formula III consists of propene derivatives of the formula I wherein
B stands for tetrahydropyranyl or a group of the formula a wherein R3 represents hydroxy, benzyloxy, methoxymethoxy or tetrahydropyranyloxy. In the definition of B, a halo means a fluoro, chloro, bromo or iodo. Preferably, halo is chloro.
According to process a) of the invention, the starting compound is a propiophenone derivative of the formula V wherein A represents hydrogen, and this compound is reacted with a bromobenzene of the formula VI wherein B stands for methyl, methoxymethyl, tetrahydropyranyl or a group of the formula a wherein R3 represents a halo, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula b wherein R4 denotes benzyl. The reagents are reacted under the conditions of the Grignard's reaction.
The expression "reacted under the conditions of the Grignard's reaction" refers to the following process: a bromobenzene of the formula VI is reacted with magnesium, preferably magnesium cuttings, to obtain a Grignard's reagent that is reacted with a propiophenone derivative of the formula V, and the reaction product is hγdrolized in aqueous medium.
The Grignard's reaction is performed in any of the usual solvents such as diethyl ether, anisole, tetrahydro¬ furan etc. The preferred solvent is tetrahydrofuran. The Grignard's reagent is prepared preferably at the boiling point of the solvent employed. If necessary, the reaction of the bromobenzene derivative of the formula VI with the magnesium can be induced by the addition of an initiating reagent commonly used for this purpose such as bromine, carbon tetrachloride, magnesium bromide etc., or the magnesium cuttings are heated with some iodine.
To the Grignard's reagent, the propiophenone derivative of the formula V is added preferably under cooling or at room temperature. In general, 2 to 5 moles of the Grignard's reagent are reacted with each mole of the propiophenone derivative. Preferably, the Grignard's reagent is employed in about twice excess.
It is preferred to perform the Grignard's reaction at an indifferent gas atmosphere, for example nitrogen stream.
The product obtained by the reaction of the Grignard's reagent with the propiophenone derivative of the formula V is hydrolized in an aqueous medium. By way of illustration, the reaction product can be poured onto an aqueous hydrochloric acid or ammonium chloride solution. The hydroxypropane of the formula II formed is extracted with an organic solvent immiscible with water.
Thus, process a) of the invention results in hydroxy¬ propane derivatives of the formula II wherein B represents methyl, methoxymethyl, tetrahydropyranyl or a group of the formula a wherein R denotes benzyloxy, methoxy¬ methoxy, tetrahydropyranyl or a group of the formula b_ wherein R4 is benzyl.
According to process b) of the invention, the starting compound is a propiophenone derivative of the formula V wherein A represents methoxy, methoxymethoxy, or a group of the formula __ wherein R5 stands for a halo, and this compound is reacted with bromobenzene under the conditions of the Grignard's reaction. The Grignard's reaction is performed as described in accordance with process a). In this way, hydroxypropane derivatives of the formula II are obtained wherein B denotes methyl, methoxymethyl or a group of the formula a wherein R3 stands for a halo.
If desired, a hydroxypropane derivative of the formula II obtained by process a) or b) is transformed into another compound of the formula II within the definition of B given in relation to formula III. The transformation is performed by the conventional methods of the preparative organic chemistry. For example, a compound of the formula II wherein B denotes a group of the formula a wherein R3 stands for benzyloxy, can be catalytically hydrogenized to obtain a compound of the formula II wherein R3 is hydroxy; or a compound of the formula II wherein B represents a group of the formula a wherein R3 is a group of the formula b wherein R4 represents benzyl, can be also hydrogenized in the presence of a suitable catalyst to obtain the corresponding compound of the formula II wherein R4 is hydrogen; or a compound of the formula II wherein B stands for a group of the formula a wherein R3 represents a chloro, can be reacted with 2-aminoethanol to obtain a compound of the formula II wherein B repesents a group of the formula b_ wherein R4 is hydrogen; or a compound of the formula II wherein B denotes tetrahydro¬ pyranyl, can be treated with a mineral acid to obtain the corresponding compound of the formula II wherein B is hydrogen. Of course, other transformations can be also performed within the definition of B in a manner known p_e_r
The propene derivatives of the formula I are prepared from the hydroxypropane derivatives of the formula II wherein B is as defined in relation to formula III by dehydration with an acid treatment. For the dehydration both mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid etc. and organic acids such as oxalic acid or p-toluenesulfuric acid etc. can be used. Preferably hydrochloric acid is employed. The dehydration of the compounds of the formula II proceeds in a wide temperature range, however, a temperature between room temperature and 120 °C is used, in general. The reaction can be performed in the presence or absence of a solvent. Aliphatic alcohols such as methanol or ethanol are preferred as solvent.
If desired, a propene derivative of the formula I is converted to another compound of the formula I within the definition of B given in relation to formula III by the usual methods of the preparative organic chemistry. Similar methods can be employed as at the transformations of the hydroxypropane derivatives of the formula II. For example, a compound of the formula I wherein B denotes a group of the formula a wherein R is hydroxy, can be reacted with thionyl chloride to obtain a compound of the formula I wherein R3 stands for chloro; or a compound of the formula I wherein B represents a group of the formula a wherein R3 is benzyloxy, can be hydrogenized in the presence of a suitable catalyst to obtain a corresponding compound of the formula I wherein R3 denotes hydroxy.
The transformation of substituent B of the compound of the formula II and the dehydration of the transformed product or the dehydration of a compound of the formula II and the transformation of substituent B of the compound of the formula I obtained can be performed simultaneously, without the separation of the intermediates. For example, a hydroxypropane derivative of the formula II wherein B represents a group of the formula a wherein R3 is tetra¬ hydropyranyloxy or methoxymethoxy, can be treated with a mineral acid to obtain a propene derivative of the formula I wherein R3 stands for hydroxy; or a hydroxypropane derivative of the formula II wherein B denotes methoxy¬ methyl, can be treated with a mineral acid to obtain a propene derivative of the formula I wherein B is hydrogen; or a hydroxypropane derivative of the formula II wherein B represents methyl, can be treated with pyridinium chloride at a high temperature to obtain a propene derivative of the formula I wherein B stands for hydrogen.
The Grignard's reaction employed according to the process of the invention is highly stereoselective. In case of process a), the hydroxypropane derivative of the formula II formed consists of primarily an isomer pair of the configuration (1RS, 2RS), however, another isomer pair of the configuration (1RS, 2SR) is also present in minor quantities. In case of process b), a diastereomeric mixture of the formula II is obtained that consists of mainly an isomer pair of the configuration (1 RS, 2SR).
Suitably, as the first step, from the diastereomeric mixture, the main product is separated, then dehydrated to obtain the corresponding propene derivative of the formula I. Another possibility consists in the dehydration of the diastereomeric mixture. Anyway, from the geometrical isomer mixture of the propene derivative of the formula I obtained, the required isomer (E) is separated by conventional methods such as fractionated crystallization.
A third aspect of the invention refers to novel 2-phenyl-3,3,3-trifluoropropiophenone derivatives of the formula V wherein A represents hydrogen, hydroxy, methoxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula
O-CH2-CH2-R d
wherein R denotes a halo, hydroxy or benzyloxy. Compounds of the formula V are starting compounds for the Grignard's reaction of the invention, thus, they are valuable intermediates for the synthesis of panomifen.
Compounds of the formula V contain a chiral (i.e. asymmetrical) carbon atom, consequently the compounds can exist in the form of optically active isomers, too. The invention includes the optical isomers and any possible mixtures thereof such as the racemates.
The compounds of the formula V are prepared from the 2-phenyl-3,3,3-trifluoropropionic acid of the formula
Figure imgf000015_0001
or a reactive derivative thereof by Friedel-Crafts' reaction. Suitably, the acid chloride of the formula
Figure imgf000015_0002
is used as the starting compound and reacted with a benzene derivative of the formula
Figure imgf000015_0003
wherein A is as defined above, in the presence of a Friedel-Crafts' catalyst.
The Friedel-Crafts' catalyst can be an inorganic salt of the type Lewis' acid e.g. aluminium trichloride, zinc chloride, boron trifluoride etc. or a mineral acid, especially sulfuric acid. Preferably anhydrous aluminium trichloride is employed as the catalyst. The Friedel-Crafts' catalyst is generally used in stoichiometric amount or up to 30 per cent excess referring to the starting compound of the formula VII or a reactive derivative thereof.
The Friedel-Crafts' reaction is performed in a suitable organic solvent such as an aromatic hydrocarbon e.g. benzene; a halogenated hydrocarbon e.g. dichloroethane, trichloroethylene or tetrachloroethylene; nitrobenzene, nitromethane, carbon disulfide etc. or mixtures thereof. It is preferred to employ benzene or nitromethane as the organic solvent.
In general, the Friedel-Crafts' reaction is performed at 0 to 50 °C, preferably at 10 to 15 °C.
If the Friedel-Crafts' reaction results in a 2-phenyl- -3,3,3-trifluoropropiophenone derivative of the formula V wherein A is other than hydrogen, it can be converted to a compound of the formula V wherein A denotes hydroxy in a manner known per se. by acidic hydrolysis or catalytical hydrogenation.
A compound of the formula V wherein A represents hydroxy can be transformed into a compound of the formula V wherein A is a substituent other than hydrogen or hydroxy in a manner known per se. for example by alkylation, benzylation or reaction with dihydropyran.
A 2-phenyl-3,3,3-trifluoroacetophenone of the formula V wherein A stands for a group of the formula d wherein R denotes hydroxy, can be benzylized to obtain a compound of the formula V wherein R represents benzyloxy. Benzylization is performed with a benzyl halide, preferably benzyl chloride or bromide. The above transformations of the compound of the formula V can be performed by using the conventional methods of the preparative organic chemistry (Greene, Protective Groups in Organic Synthesis, 1981 ).
Thus, the 2-phenyl-3,3,3-trifluroacetophenone derivatives of the formula V are prepared by reacting 2-phenyl-3,3,3-trifluoropropionic acid of the formula VII or a reactive derivative thereof, preferably 2-phenyl-3,3,3- -trifluoropropionyl chloride of the formula VIII in the presence of a Friedel-Crafts' catalyst with a benzene derivative of the formula IX wherein A is as stated in relation to formula V and, if desired, hydrolizing a compound of the formula V wherein A is other than hydrogen or hydroxy to obtain a compound of the formula
V wherein A denotes hydroxy with an acid, or alkylating a compound of the formula V wherein A stands for hydroxy to obtain a compound of the formula V wherein A represents methoxy, benzyloxy, methoxymethoxy or a group of the formula _. wherein R is as stated above with an alkylating agent, or reacting a compound of the formula
V wherein A is hydroxy with dihydropyran to obtain a compound of the formula V wherein A represents tetra¬ hydropyranyloxy, or reacting a compound of the formula V wherein A is hydroxy with a benzyl halide to obtain a compound of the formula V wherein A is benzyloxy, or reacting a compound of the formula V wherein A stands for a group of the formula d wherein R is hydroxy with a benzene halide to obtain a compound of the formula V wherein R represents benzyloxy.
The optically active compounds of the formula V can be prepared from the corresponding racemic compounds by conventional resolution methods. Various mixtures can be prepared from the optically active isomers.
The starting 2-phenyl-3,3,3-trifluoropropionic acid of the formula VII is a known compound /Dale et al., J. Org. Chem., 3 , 2543-2549 (1969)/. The preferred reactive derivative thereof i.e. 2-phenyl-3,3,3-trifluoropropionyl chloride of the formula VIII is prepared from the carboxylic acid of the formula VII with an inorganic acid chloride such as thionyl chloride, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, suitably in the absence of a solvent. The inorganic acid chloride is used in an equimolar amount or suitably in an excess. The reaction is performed at a temperature between room temperature and the boiling point of the inorganic acid chloride used. The excess of the inorganic acid chloride is distilled off and the remaining compound of the formula VIII is used in the Friedel-Crafts' reaction.
The benzene derivatives of the formula IX are commercially available or can be easily prepared by the usual methods of organic chemistry.
The bromobenzene derivatives of the formula VI used for the Grignard's reaction are partly known compounds /J. Am. Chem. Soc, 42, 163 (1920); EP No. 463 199; J. Steroid. Biochem., 23, 233-245 (1987); J. Chem. Soc, 69. 165 (1900)/ and some of them are commercially available. The preparation of the novel compounds of the formula VI is shown in the description.
The process of the invention for the preparation of compounds of the formula III is highly economical. Compounds of the formula V can be prepared with a yield of about 70 %. The compounds of the formula II can be obtained by the Grignard's reaction with a yield of 75 % and they can be converted to the compounds of the formula I with a yield of 90 to 100 %.
The invention is further elucidated by means of the following Examples.
Preparation of starting compounds of the formula VI 1. 4-[2-(Methoxymethoxy)ethoxy]-bromobenzene
177.45 g (2.33 moles; 250 cm3) of formaldehyde dimethyl acetal are added, drop by drop, to 7.5 g (0,035 moles) of 2-(4-bromophenoxy)ethanol /preparation: J. Am. Chem. Soc, 42, 163/ dissolved in 150 cm3 of chloroform at 25 to 30 °C. Then, to the reaction mixture cooled to 20 °C, 100.6 g (0.71 moles) of phosphorus pentoxide are added at a rate that maintains the temperature at 20 to 25 °C. The reaction mixture is stirred for 45 minutes, then poured to 500 cm3 of 10 per cent aqueous sodium carbonate solution at 10 to 15 °C under stirring. The mixture is extracted 6 times using 200 cm3 of chloroform each time, the organic phase is washed twice with 500 cm3 of 10 per cent aqueous sodium chloride solution each time, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil is fractionated to obtain 4,0 g (44 %) of the title compound. B.p.: 154-160 °C at 4 mm Hg.
Analysis for C10H1 3BrO3 (261.12) calculated: C 45.39 %, H 5.02 %, Br 30.60 %; found: C 45.22 %, H 4,94 %, Br 30.37 %. n*5 = 1.5286.
1 H-NMR (250 MHz, CDCI3) ppm: 7.37 (d, 2H, J 8.9 Hz); 6.81 (d, 2H, J 9.1 Hz); 4.71 (s. 2H); 4.1 1 (t, 2H, J 4.4 Hz); 3.9 (t, 2H, J 4.5 Hz); 3.39 (s, 3H). 2. N-(2-Hydroxyethyl)-4-(2-aminoethoxy)-bromobenzene 28.3 g (0.12 moles) of 4-(2-chloroethoxy)-bromo- benzene /preparation: J. Chem. Soc, 33, 165 (1900)/ are dissolved in 120 cm3 of 2-methoxyethanol at 25 °C. To the solution obtained, 73.3 g (0.19 moles) of 2-amino- ethanol are added, drop by drop, and the reaction mixture is boiled under reflux for one hour, then cooled to room temperature. 960 cm3 of dichloromethane are added, and the mixture is washed with 200 cm3 of 4 per cent aqueous sodium hydroxide solution, then 6 times with water using 300 cm3 of water each time. The organic phase is dried over anhydrous magnesium sulfate, evaporated, and the residue is recrystallized from hexane. 20.8 g (67 %) of the title compound are obtained. M.p.: 67-68 °C.
Analysis for Cl 0H1 4BrNO (260.14) calculated: C 46.17 %, H 5.42 %, N 5,38 % Br 30.72 %; found: C 46.52 %, H 5,59 %, N 5,35 % Br 30.83 %.
1 H-NMR (80 MHz, CDCI3) ppm: 7.37 (d, 2H, J 9.1 Hz); 6.71 (d, 2H, J 8.8 Hz); 4.04 (t, 2H, J 5.1 Hz); 3.67 (t, 2H, J 5.2 Hz); 3.02 (t, 2H, J 5.1 Hz); 2.85 (t, 2H, J 5.2 Hz); 2.04 (bs, 2H).
3. N-Benzyl-N-(2-hydroxyethyl)-4-(2-aminoethoxy)- -bromobenzene
To 70 cm3 (77.2 g, 0,61 moles) of benzyl chloride, 18.2 g (0.07 moles) of N-(2-hydroxyethyl)-4-(2-amino- ethoxy)-bromobenzene, then 9.7 g (0.07 moles) of potassium carbonate are added at 25 °C under stirring. The mixture is stirred for 24 hours at the above temperature, then poured onto 350 cm3 of ice water. The mixture obtained is extracted with 150 ml of chloroform, then twice with 100 ml of chloroform each time. The organic solutions are combined, dried over anhydrous magnesium sulfate, evaporated and the residue is distilled to obtain 24.5 g (70 %) of the title compound as a pale yellow, viscous oil. B.p.: 230 °C at 4 mm Hg.
Figure imgf000021_0001
Analysis for C1 7H20BrN02 (350.27) calculated: C 58.30 %, H 5.76 %, N 4,00 % Br 22.81 %; found: C 58.12 %, H 5,78 %, N 3,94 % Br 22.73 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.4-7.2 (m, 7H); 6.71
(d, 2H, J 8.9 Hz); 3,94 (t, 2H, J 5.6 Hz); 3.74 (s, 2H);
3.58 (t, 2H, J 5.3 Hz); 2.93 (t, 2H, J 5.6 Hz); 2.76 (t, 2H,
J 5.3 Hz); 2.54 (s, 1 H).
The hydrochloride of the title compound melts at 133 to
136 °C.
4. N-Benzyl-N-(2-benzyloxyethyl)-4-(2-aminoethoxy)-
-bromobenzene
10 g (0.029 moles) of N-benzyl-N-(2-hydroxyethyl)-4- -(2-aminoethoxy)-bromobenzene are dissolved in 86 cm° of anhydrous tetrahydrofuran at 25 °C, and to the solution cooled to 0 °C, 0,84 g (0.035 moles) of sodium hydride (80 % dispersion) are added at a rate that maintains the temperature at 0 to 5 °C. The mixture is stirred for further 30 minutes, then 4.1 cm3 (4.4 g, 0.035 moles) of benzyl chloride are added, drop by drop, while maintaining the temperature at 0 to 5 °C. The reaction mixture is stirred for one hour, then allowed to reach room temperature and heated under reflux for 40 hours. The mixture cooled to room temperature is poured onto 230 cm° of ice water and extracted 3 times with 100 cm3 of chloroform each time. The organic phase is dried over anhydrous magnesium sulfate, then evaporated, the residual oil is transferred to a column filled with Kieselgel 60 and eluted with a mixture of hexane and ethyl acetate (8:2). 5.6 g (44 %) of the title compound are obtained. n ^5 = 1.5780.
Analysis for C 4H26BrNO2 (440.39) calculated: C 65.46 %, H 5.95 %, N 3,18 % Br 18.15 %; found: C 65.06 %, H 5,84 %, N 3,21 % Br 18.95 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.5-7.2 (m, 12H); 6.69 (d, 2H, J 9.0 Hz); 4,49 (s, 2H,); 3.97 (t, 2H, J 6.1 Hz); 3.76 (s, 2H); 3.59 (t, 2H, J 5.9 Hz); 2.95 (t, 2H, J 6.1 Hz); 2.86 (t, 2H, J 5.9 Hz).
Preparation of the compounds of the formula V
Example 1 2-Phenyl-3,3,3-trifluoropropiophenone
10.2 g (0.05 moles) of 2-phenyl-3,3,3-trifluoro- propionic acid are heated with 50 cm3 of thionyl chloride under reflux for one hour, then the solution is evaporated. To the residue, 20 cm3 of anhydrous benzene are added, and the solution is evaporated again. This procedure is repeated once more. The residual oil is dissolved in 10 cm3 of anhydrous benzene, and the solution obtained is added, drop by drop, to the mixture of 8.66 g (0.065 moles) of powdered anhydrous aluminium trichloride and 12 cm3 of anhydrous benzene under stirring while maintaining the temperature at 10 to 15 °C. The reaction mixture is stirred for a further hour at this temperature, then poured onto 60 g of ice, and extracted 3 times with 50 cm3 of chloroform each time. The organic solutions are combined, washed with 15 cm3 of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated. The residual oil is crystallized from benzene to obtain 9.3 g (70 %) of the title compound.
M.p.: 81-82 °C; b.p.: 130-134 °C at 2 mm Hg.
Analysis for C1 5H1 F3 (264.25) calculated: C 68.18 %, H 4.20 %, F 21.57 %; found: C 68.07 %, H 4,17 %, F 21.42 %.
IR (KBr): 1690, 1143 cm"1.
1 H-NMR (CDC13) ppm: 7.92-7.88 (m, 2H); 7.54-7.35 (m,
8H); 5,30 (q, 1 H, JH F 8.2 Hz).
1 3C-NMR (CDCI3) ppm: 191.2; 135.3; 133.8; 129.8;
129.6; 129.3; 129.2; 128.8; 124.3 (q, JCF 280.2 Hz);
56.4 (q, JCF 26.6 Hz).
Example 2 1 -Methoxy-4-(2-phenyl-3,3,3-trifluoropropionyl)-benzene
8.48 g (0.038 moles) of 2-phenyl-3,3,3-trifluoro- propionyl chloride are dissolved in 23 cm3 (22.82 g, 0.21 moles) of anhydrous anisole, and to the stirred solution obtained, 12.19 g (0.09 moles) of powdered, anhydrous aluminium trichloride are added. The mixture becomes 50 °C, then it is heated to 75 °C, stirred for 1.5 hours at this temperature, and cooled to room temperature (i.e. 25 °C). The mixture is poured onto 80 g of crushed ice, extracted 3 times with 50 cm3 of dichloromethane each time, the organic solutions are combined, washed twice with 40 cm3 of water each time treated with active carbon, and evaporated. The residual brown oil (1 1 .2 g) is transferred to a Kieselgel 60 column, and eluted with toluene. The solvent is evaporated, and the residual pale yellow oil is crystallized from kerosene at 10 °C to obtain 2.4 g (22 %) of the title compound. M.p.: 62-64 °C.
Analysis for C1 6H1 3F3θ2 (294.28) calculated: C 65.30 %, H 4.45 %; found: C 65.13 %, H 4.58 %.
IR (KBr): 1681 , 1 114, 1 101 , 846, 763, 703 cm" 1.
1 H-NMR (CDC13) ppm: 7.88 (d, 2H, J 9.1 Hz); 7.5-7.3
(m, 5H); 6.86 (d, 2H, J 8.9 Hz); 5.24 (q, 1 H, JHF 8.3 Hz);
3.80 (s, 3H).
1 3C-NMR (CDCI3) ppm: 189.7; 164.1 ; 131.2; 130.1 ;
129.8; 129.2; 129.1 ; 128.3; 124.4 (q, JCF 280.2 Hz);
1 14.0; 56.0; (q, JCF 24.4 Hz); 53.3.
Example 3 1-(2-Chloroethoxy)-4-(2-phenyl-3,3,3-trifluoropropionyl)- -benzene
6.23 g (0.028 moles) of 2-phenyl-3,3,3- trifluoropropionyl chloride and 8.77 g (0.056 moles) of 2- chloroethoxybenzene are dissolved in 28 cm3 of nitromethane, and the flask containing the solution obtained is immersed into a water bath at 20 °C. 9.0 g (0.067 moles) of powdered anhydrous aluminium tri¬ chloride are added to the stirred solution, the flask is sealed by means of a tube containing calcium chloride and allowed to warm to 25 °C while keeping it in the water bath. The contents of the flask is stirred for 4 hours, then poured onto 50 g of ice, and extracted twice with 20 cm3 of diethyl ether each time. The combined organic phases are dried over anhydrous magnesium sulfate, the diethyl ether is distilled off, then also the nitromethane is removed under reduced pressure. The residual yellow oil is transferred to a Kieselgel 60 column, and eluted with a mixture of hexane and ethyl acetate (45:7). 5.4 g (56 %) of the title compound are obtained. M.p.: 61-63 °C. B.p. : 210-215 °C at 5 mm Hg. Analysis for C1 7H1 ciF3O2 (342.75) calculated: C 59.57 %, H 4.12 % Cl 10.34 %; found: C 59.45 %, H 4.15 % Cl 10.25 %.
1 H-NMR (CDC13) ppm: 7.88 (d, 2H, J 8.9 Hz); 7.55-7.35 (m, 5H); 6.88 (d, 2H, J 8.9 Hz); 5.23 (q, 1 H, JHF 8.3 Hz); 4.24 (t, 2H, J 5.8 Hz); 3.79 (t, 2H, 5.8 Hz).
Example 4 1-Hydroxy-4-(2-phenyl-3,3,3-trifluoropropionyl)-benzene
13.3 g (0.10 moles) of anhydrous aluminium tri¬ chloride are added, in portions, to the solution of 4.7 g (0.05 moles) of phenol in 50 cm3 of anhydrous dichloro¬ methane at 10 °C. To the mixture, 1 1 .3 g (0.05 moles) of 2-phenyl-3,3,3-trifluoropropionyl chloride are added, drop by drop, at a rate that maintains the temperature of the mixture at 8 to 10 °C. The reaction mixture is stirred for 1.5 hours, then poured onto 300 g of ice, and extracted 3 times with 50 cm3 of chloroform each time. The organic phases are combined, dried over anhydrous magnesium sulfate, and evaporated. The residue is transferred to a column with Kieselgel 60 that is eluted with a mixture of ethyl acetate and n-hexane (3:7). 5.6 g (40 %) of the title compound are obtained as white crystals. M.p.: 156-159 °C. Analysis for C1 5H1 1 F3O2 (280.25) calculated: C 64.29 %, H 3.96 %; found: C 64.55 %, H 3.94 %.
1 H-NMR (CDCI3) ppm: 7.84 (d, 2H, J 8.9 Hz); 7.4 (m, 5H); 6.82 (d, 2H, J 8.9 Hz); 6.05 (br s, 1 H); 5.22 (q, 2H, J 8.3). Example 5 1 -Hydroxy-4-(2-phenyl-3,3,3-trifluoropropionyl)benzene
A mixture of 3.8 g (0.013 moles) of 1-methoxy-4-(2- -phenyl-3,3,3-trifluoropropionyl)benzene, 41 cm3 of bi- -distilled 49 per cent hydrogen bromide and 10 cm3 of glacial acetic acid is boiled (at 122 °C) for 12 hours. The reaction mixture is cooled to room temperature (i.e. 25 °C), the product separated is filtered, washed with water, and dried. 1.57 g of solid product are obtained that is dissolved in 1.5 cm3 of isopropanol under heating, then precipitated with water, filtered, and washed with kerosene to yield 1.5 g (41 %) of the title compound. M.p.: 151-154 °C.
Example 6
1 -(2-Hydroxyethyloxy)-4-(2-phenyl-3,3,3-trifluoro- propionyDbenzene
2.66 g (0.02 moles) of aluminium trichloride are added to the solution of 1.4 g (0.01 moles) of 2-phenoxy- ethanol in 30 cm3 of anhydrous dichloromethane at 8 to 10 °C. To the mixture obtained, 2.2 g (0.01 moles) of 1 , 1 ,1-trifluoro-2-phenylpropionyl chloride are added, drop by drop, at the same temperature. The reaction mixture is stirred for 8 hours at the same temperature, left to stand for a night, then poured onto 100 g of crushed ice. The aqueous mixture is extracted 3 times with 30 cm3 of chloroform each time, the combined organic phases are washed twice with 25 cm3 of water each time, then dried over anhydrous magnesium sulfate, and evaporated. The residue consists of about 3 g of greenish-yellow oil that is transferred to a column filled with Kieselgel 60. The column is eluted with a mixture of kerosene and ethyl acetate (7:3) to obtain 1.3 g (40 %) of colourless oil that crystallizes on standing. The crystalline product is treated with 10 cm3 of kerosene, filtered, and washed with kerosene containing 5 per cent of isopropanol. In this way,
1.1 g (34 %) of the title compound are obtained as a snow-white powder. M.p.: 64-66 °C.
Analysis for C-1 H-J 5F3O3 (324.31 ) calculated: C 62.96 %, H 4.66 %; found: C 62.63 %, H 4.72 %.
1 H-NMR (CDCI3) ppm: 7.87 (d, 2H, J 9.0 Hz); 7.47-7.35
(m, 5H); 6.88 (d, 2H, J 8.8 Hz); 5.23 (q, 1 H, JHF 8.3 Hz);
4.15-4.05 (m, 2H); 3.96 (bs, 2H); 2.05 (bs, 1H).
Example 7 1-(Methoxymethoxy)-4-(2-phenyl-3,3,3-trifluoropropionyl)- benzene
1 1.1 g (12.1 cm3, 0.146 moles) of formaldehyde dimethyl acetate are added, drop by drop, to the solution of 1.8 g (0.006 moles) of 1-hydroxy-4-(2-phenyl-3,3,3-tri- fluoropropionyDbenzene in 35 cm3 of chloroform at 10 to 15 °C. To the mixture obtained, 4.87 g (0.034 moles) of phosphorus pentoxide are added in portions maintaining the temperature within the above range. The reaction mixture is stirred for 15 minutes at this temperature, left to reach room temperature, stirred for further 6 hours at this temperature, then poured to 100 cm3 of 10 per cent aqueous sodium carbonate solution at 10 to 15 °C, and the mixture is extracted 4 times with 50 cm3 of chloro¬ form each time. The organic layers are combined, washed twice with 90 cm3 of 10 per cent aqueous sodium chloride solution each time, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residual yellow oil crystallizes on cooling. The crystals are washed with kerosene to obtain 1.4 g (69.2 %) of the title compound as a white powder. M.p.: 63-65 °C.
Analysis for C1 7H1 5F.3O3 (324.31 ) calculated: C 62.95 %, H 4.66 %; found: C 62.59 %, H 4.64 %.
1 H-NMR (CDC13) ppm: 7.87 (d, 2H, J 8.9 Hz); 7.5-7.3
(m, 5H); 7.00 (d, 2H, J 8.9 Hz); 5.20 (s, 1 H, JHF 8.1 Hz);
5.18 (s, 2H); 3.43 (s, 3H).
Example 8 1 -(2-Tetrahydropyranyloxy)-4-(2-phenyl-3,3,3-trifluoro- propionyDbenzene
To the solution of 7.52 g (7 cm3, 0,089 moles) of 3,4-dihydro-2H-pyran in 50 cm3 of chloroform, one drop of concentrated hydrochloric acid, then, after 10 minutes, 1.4 g (0.05 moles) of 1-hydroxy-4-(2-phenyl-3,3,3-tri- fluoropropionyDbenzene are added. The reaction mixture is stirred for 5 minutes, then washed with saturated aqueous sodium hydrogen carbonate solution, treated with active carbon, filtered, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with a mixture of ethyl acetate and n-hexane (3:7). The solution obtained after elution is evaporated, the residual crystals are washed with 5 cm3 of kerosene, and dried to obtain 1.3 g (70 %) of the title compound. M.p.: 145-150 °C. Analysis for C20H1 9F3θ3 (364.37) calculated: C 65.93 %, H 5.26 %; found: C 65.85 %, H 5.39 %.
1 H-NMR (CDCI3) ppm: 7.86 (d, 2H, J 8.9 Hz); 7.5-7.3 (m, 5H); 7.02 (d, 2H, J 8.8 Hz); 5.46 (bs, 1 H); 5.23 (q, 1 H, JHF 8.28 Hz); 3.9-3.7 (m, 1 H); 3.65-3.5 (m, 1 H); 2.1 -1.5 (m, 6H). Preparation of the compounds of the formula III
Example 9 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -(4- -methoxyphenyOpropane
A mixture of 4.26 g (22.8 mmoles) of 4-bromo- anisole, 0.55 g (22.6 mmoles) of magnesium cuttings and 23 cm3 of anhydrous tetrahydrofuran is boiled for one hour under reflux to obtain the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 2.01 g (7.6 mmoles) of 2-phenyl-3,3,3-trifluoropropiophenone in 8 cm3 of anhydrous tetrahydrofuran are added while maintaining the temperature at 20 to 25 °C. The reaction mixture is stirred for one hour at 25 °C, then poured onto 100 cm3 of 0.5 M aqueous hydrochloric acid cooled to 10 °C, and extracted twice with 50 cm3 of dichloromethane each time. The organic layers are combined, washed with 50 cm3 of water, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with toluene. The product is crystallized from isopropanol to obtain 1.12 g (40 %) of the title compound. M.p.: 85-87 °C.
Analysis for C2 H1 9F3O3 (372.40) calculated: C 70.96 %, H 5.14 %; found: C 70.74 %, H 5.20 %. H-NMR (250 MHz, CDCl3) ppm: 7.58 (d, 2H, J 8.8 Hz); 7.45-6.9 (m, 10H); 6.88 (d, 2H, J 8.8 Hz); 4.58 (q, 1 H, JH F 9.2 Hz); 3.77 (s, 3H); 2.81 (s, 1 H). Example 10 1 RS,2SR-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -(4- -methoxyphenyDpropane
A mixture of 1.60 g (10.2 mmoles) of bromobenzene, 0.25 g (10.3 mmoles) of magnesium cuttings and 12 cm3 of anhydrous tetrahydrofuran is boiled under reflux for one hour to yield the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 1.00 g (3.4 mmoles) of 4-(2- -phenyl-3,3,3-trifluoropropionyl)anisole in 4 cm3 of anhydrous tetrahydrofuran are added while maintaining the temperature of the mixture at 20 to 25 °C. The reaction mixture is stirred at 25 °C for one hour, then poured onto 50 cm3 of 0.5 M hydrochloric acid at 10 °C. The mixture obtained is extracted twice with 25 cm3 of dichloro¬ methane each time, the organic layers are combined, washed with 25 cm3 of water, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with toluene. The product is crystallized from isopropanol to obtain 0.42 g (33 %) of the title compound. M.p.: 1 18-1 19 °C. Analysis for C22H1 9F3O3 (372.40) calculated: C 70.96 %, H 5.14 %; found: C 71.1 1 %, H 5.19 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.65 (d, 2H, J 7.6 Hz); 7.45-7.1 (m, 10H); 6.59 (d, 2H, J 8.9 Hz); 4.59 (q, 1 H, JH F 9.2 Hz); 3.62 (s, 3H); 2.82 (s, 1 H).
Example 1 1 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1-(4- -methoxymethoxyphenyDpropane
A mixture of 3.26 g (16.0 mmoles) of 4-(methoxy- methoxy)-bromobenzene, 0,36 g (14.8 mmoles) of magnesium cuttings and 15 cm3 of anhydrous tetrahydro- PO7HU95/00056
29
furan is boiled under reflux for one hour to obtain the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 1.32 g (5.0 mmoles) of 2-phenyl-3,3,3-tri- fluoropropiophenone in 5 cm3 of anhydrous tetrahydro¬ furan is added while maintaining the temperature of the reaction mixture at 20 to 25 °C. The mixture is stirred for one hour at 25 °C, then poured onto 80 cm3 of 0.5 M aqueous ammonium chloride solution at 10 °C, and extracted twice with 40 cm3 of dichloromethane each time. The organic layers are combined, washed with 40 cm3 of water, and evaporated. The residue that crystallizes is transferred to a filter, and washed three times using 0.5 cm3 of ethanol each time to obtain 1.01 g (50 %) of the title compound. M.p.: 1 16-117 °C. Analysis for C 3H21 F3O3 (402.42) calculated: C 68.65 %, H 5.26 %; found: C 68.50 %, H 5.17 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.60 (d, 2H, J 8.9 Hz); 7.4-6.9 (m, 12H); 5.15 (s, 2H); 4.59 (q, 1 H, JH F 9.2 Hz); 3.45 (s, 3H); 2.84 (s, 1 H).
Example 12 1 RS,1 SR-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1-(4- -methoxymethoxyphenyDpropane
A mixture of 1.07 g (6.8 mmoles) of bromobenzene, 0.17g (7.0 mmoles) of magnesium cuttings and 7 cm3 of anhydrous tetrahydrofurane is boiled under reflux for one hour to obtain the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 0.74 g (2.3 mmoles) of 4- -(2-phenyl-3,3,3-trifluoropropionyl)-1-(methoxymethoxy)- benzene in 3 cm3 of anhydrous tetrahydrofuran are added while maintaining the temperature of the reaction mixture at 20 to 25 °C. The mixture is stirred for one hour at 25 °C, then poured onto 35 cm3 of 0.5 M hydrochloric acid at 10 °C, and extracted twice using 20 cm3 of dichloro-methane each time. The organic layers are combined, washed with 20 cm3 of water, and evaporated. The residual yellow oil is transferred to a column filled with silica gel, and eluted with toluene. The product is recrystallized from isopropanol to obtain 0.43 g (47 %) of the title compound. M.p.: 109-1 10 °C. Analysis for C23H21 F3θ3 (402.42) calculated: C 68.65 %, H 5.26 %; found: C 68.93 %, H 5.27 %.
1 H-NMR (250 MHz, CDCl3) ppm: 7.65 (d, 2H, J 7.7 Hz); 7.5-7.0 (m, 10H); 6.72 (d, 2H, J 8.7 Hz); 4.99 (s, 2H); 4.59 (q, 1 H, JH F 9.1 Hz); 3.34 (s, 3H); 2.85 (s, 1 H).
Example 13 1 RS,2SR-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -[4-(2- -chloroethoxy)phenyl]propane
A mixture of 1 .88 g (12.0 mmoles of bromobenzene, 0.29 g (11.9 mmoles) of magnesium cuttings and 12 cm3 of anhydrous tetrahydrofuran is boiled for one hour under reflux to obtain the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 1.36 g (4.0 mmoles) of 1 -(2-chloroethoxy)-4-(2-phenyl-3,3,3-trifluoropropionyl)- benzene in 8 cm3 of anhydrous tetrahydrofuran are added while maintaining the temperature at 20 to 25 °C. The mixture is stirred for 2 hours at 25 °C, then poured onto 60 cm3 of 0.5 M hydrochloric acid, and extracted twice with 30 cm3 of dichloromethane each time. The organic layers are combined, washed with 30 cm3 of water, and n evaporated. The residue is recrystallized from 1 1 c J of isopropanoi to obtain 1 .01 g (60 %) of the title compound. M.p.: 128-130 °C. Analysis for C23H2oCIF3θ3 (420.86) calculated: C 65.64 %, H 4.79 % Cl 8.42 %; found: C 65.90 %, H 4.75 % Cl 8.28 %.
1H-NMR (250 MHz, CDCl3) ppm: 7.66 (d, 2H, J 7.6 Hz); 7.5-7.1 (m, 10H); 6.60 (d, 2H, J 8.9 Hz); 4.59 (q, 1 H, JH F 9.2 Hz); 4.03 (t, 2H, J 5.9 Hz); 3.67 (t, 2H, J 5.9 Hz); 2.83 (s, 1H).
Example 14 1RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1-[4-(2- -benzyloxyethoxy)phenyl]propane
A mixture of 2.50 g (8.1 mmoles) of 4-(2-benzyloxγ- ethoxy)bromobenzene, 0.20 g (8.2 mmoles) of magnesium cuttings and 8 cm3 of anhydrous tetrahydrofuran is boiled for one hour under reflux to obtain the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 0.72 g (2.7 mmoles) of 2-phenyl-3,3,3-trifluoropropiophenone in 3 cm° of anhydrous tetrahydrofuran are added while maintaining the temperature at 20 to 25 °C. The reaction mixture is stirred for one hour at 25 °C, then poured onto 40 cm3 of 0.5 M hydrochloric acid, and extracted three times using 20 cm3 of dichloromethane each time. The organic layers are combined, washed with 20 cm3 of water, and evaporated. The residual yellow oil is transferred to a column containing Kieselgel 60, and eluted with a mixture of toluene and ethyl acetate (95:5). The product is recrystallized from isopropanol to obtain 1.00 g (75 %) of the title compound. M.p.: 123-125 °C. Analysis for C3oH27F3θ3 (492.55) calculated: C 73.16 %, H 5.53 %; found: C 73.00 %, H 5.60 %. 1 H-NMR (250 MHz, CDClg) ppm: 7.57 (d, 2H, J 8.9 Hz); 7.4-6.9 (m, 15 H); 6.90 (d, 2H, J 8.9 Hz); 4.61 (s, 2H); 4.57 (q, 1 H, JH F 9.2 Hz); 4.2-4.1 (m, 2H); 3.85-3.75 (m, 2H); 2.80 (s, 1 H).
Example 15 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -{4-[2- -(methoxymethoxy)ethoxy]phenyl}propane
A mixture of 10.0 g (38 mmoles) of 4-(2-methoxy- methoxyethoxyjbromobenzene, 0.93 g (38 mmoles) of magnesium cuttings and 38 cm3 of anhydrous tetrahydro¬ furan is boiled for one hour under reflux to yield the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 3.37 g (13 mmoles) of 2-phenyl-3,3,3-tri- q fluoropropiophenone in 13 cm° of anhydrous tetrahydro¬ furan are added while maintaining the temperature at 20 to 25 °C. The reaction mixture is stirred for one hour at 25 °C, then poured onto 200 cm3 of 0.5 M hydrochloric acid at 10 °C, and extracted twice with 100 cm3 of dichloro¬ methane each time. The organic layers are combined, washed with 100 cm3 of water, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with a mixture of toluene and ethyl acetate (95:5). In this way, 4.27 g (75 %) of the title compound are obtained. M.p.: 100-102 °C. Analysis for C25H25F3O (446.48) calculated: C 67.26 %, H 5.64 %; found: C 67.44 %, H 5.64 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.58 (d, 2H, J 8.9 Hz); 7.4-6.95 (m, 10H); 6.91 (d, 2H, J 8.9 Hz); 4.69 (s, 2H); 4.57 (q, 1 H, JH F 9.2 Hz); 4.15-4.1 (m, 2H); 3.9-3.85 (m, 2H) 3.38 (s, 3H); 2.85 (s, 1 H). Example 16 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1-{4-[2-(2- -tetrahydropyranyloxy)ethoxy]phenyl}propane
0.44 g (17.9 mmoles) of magnesium cuttings are heated with a small crystal of iodine to obtain activated magnesium that is boiled with a solution of 5.39 g (17.9 mmoles) of 4-[2-(2-tetrahydropyranyloxy)ethoxy]bromo- benzene in 18 cm3 of anhydrous tetrahydrofuran under reflux. After about 15 minutes, the formation of the Grignard's reagent is started. After 1.5 hours, the chief part of magnesium is dissolved. To the mixture cooled to 20 °C, a solution of 1.89 g (7.2 mmoles) of 2-phenyl- -3,3,3-trifluoropropiophenone in 7 cm3 of anhydrous tetrahydrofuran are added while maintaining the temperature at 20 to 25 °C. The reaction mixture is stirred for one hour at 25 °C, then poured onto 100 cm3 of 0.5 M aqueous ammonium chloride solution at 10 °C, and extracted 3 times with 50 cm3 of diethyl ether each time. The organic layers are combined, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. From the residue, 140 cm3 of water are distilled q off, and the residual oil is crystallized from 17 cm° of isopropanol to obtain 2.13 g (61 %) of the title compound.
M.p.: 111-114 °C.
Analysis for C 8H29F3θ4 (486.54) calculated: C 69.12 %, H 6.01 %; found: C 68.88 %, H 5.70 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.58 (d, 2H, J 8.8 Hz);
7.45-6.9 (m, 10H); 6.91 (q, 1 H, J 8.8 Hz); 4.69 (t, 1 H, H
3.3 Hz); 4.58 (q, 1 H, JH F 9.2 Hz); 4.13 (t, 2H, J 4.8 Hz);
4.1-4.0 (m, 1 H); 3.95-3.75 (m, 2H); 3.55-3.45 (m, 1 H);
2.86 (s, 1 H); 1 .9-1 .4 (m, 6H). Example 17 1 ,2-Diphenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)propene
0.50 g (1 .3 mmoles) of 1 RS,2RS- or 1 RS,2SR-1 ,2- -diphenyl-1 -hydroxy-3,3,3-trifluoro-1-(4-methoxyphenyl)- propene are heated under reflux in a mixture of 5 cm3 of ethanol and 1 cm3 of concentrated hydrochloric acid for 30 minutes. The reaction mixture is poured onto 10 cm3 of water, and extracted twice with 5 cm3 of dichloro¬ methane each time. The organic layers are combined, washed with 5 cm3 of water, and evaporated to obtain 0.43 g (90 %) of the title compound. The isomeric ratio (E)/(Z) = 7.1 :1 .
1 H-NMR (250 MHz, CDCI3) ppm: 7.4-7.15 (m, E 10H + Z 7H); 7.05-7.0 (m, Z 3H); 6.95-6.85 (m, Z 4H); 6.81 (d, E 2H J 8.9 Hz); 6.54 (d, E 2H, J 9.0 Hz); 3.80 (s, Z 3H); 3.64 (s, E 3H).
Example 18 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1 -[4-(2-chloroethoxy)- phenyllpropene
1.10 g (2.6 mmoles) of 1RS,1 SR-1 ,2-diphenyl-1 - -hydroxy-3,3,3-trifluoro-1-[4-(2-chloroethoxy)phenyl]- propane are heated under reflux in a mixture of 22 cm3 of methanol and 4.4 cm3 of concentrated hydrochloric acid for one hour, then the reaction mixture is cooled to 0 °C. The crude product that crystallizes is filtered, and recrystallized from 14 cm3 of methanol to obtain 0.80 g (76 %) of the title compound as white crystals. The content of (Z) isomer is lower than 1 %. M.p.: 107-109 °C.
Analysis for C23H1 8C1F303 (402.85) calculated: C 68.58 %, H 4.50 % Cl 8.80 %; found: C 69.00 %, H 4.53 % Cl 8.49. 1 H-NMR (250 MHz, CDCI3) ppm: 7.45-7.1 (m, 10H); 6.82 (d, 2H, J 8.8 Hz); 6.56 (d, 2H J 8.8 Hz); 4.06 (t, 2H J 5.9 Hz); 3.69 (t, 2H J 5.9 Hz).
Example 19 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-chloroethoxy)- phenyllpropene
1.15 g (3.0 mmoles) of <E)-1 ,2-diphenyl-3,3,3-tri- f luoro-1 -[4-(2-hydroxyethoxy)phenyl]propene /(E)-isomer content is higher than 97 %/ are boiled in 3.5 cm3 of thionyl chloride in the presence of 2 drops of pyridine for 3 hours. The solution is evaporated, the last traces of thionyl chloride are removed by adding and distilling off benzene. The crude product obtained is recrystallized from 13 cm3 of methanol to obtain 1.05 g (87 %) of the title compound. The content of (Z) isomer is lower than 1 %. M.p.: 108-109 °C.
Example 20 1 ,2-diphenyl-3,3,3-trifluoro-1 -(4-(2-benzyloxyethoxy)- phenyljpropene
0.60 g (1.2 mmoles) of 1RS,2RS-1 ,2-diphenyl-1- -hydroxy-3,3,3-trifluoro-1-[4-(2-benzyloxyethoxy)phenyl]- propene are boiled in a mixture of 6 cm3 of ethanol and 1.2 cm3 of concentrated hydrochloric acid for 30 minutes. The mixture is poured onto 15 cm3 of water, and extracted twice with 5 cm3 of dichloromethane each time. q
The organic layers are combined, washed with 5 cm° of water, and evaporated to obtain 0.58 g (100 %) of the title compound. The isomeric ratio (E)/(Z) = 7.3:1 . 1 H-NMR (250 MHz, CDCI3) ppm: 7.4-7.15 (m,E 15H + Z 12H); 7.05-7.0 (m, Z 3H); 6.95-6.85 ( , Z 4H); 6.79 (d, E 2H, J 8.8 Hz); 6.56 (d, E 2H, J 8.8 Hz); 4.64 (s, Z 2H); 4.56 (s, E 2H); 4.2-4.15 (m, Z 2H); 4.0-3,95 (m, E 2H); 3.85-3.8 (m, Z 2H); 3.75-3.65 (m, E 2H).
Example 21 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -[4-(2- -hydroxyethoxy)phenyl]propane
1 .00 g (2.0 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1- -hydroxy-3,3,3-trifluoro-1-[4-(2-benzyloxyethoxy)phenyl]- propane is hydrogenized in 25 cm3 of methanol in the presence of 0.2 g of 10 per cent palladium/carbon catalyst at 25 °C and atmospheric pressure for 7 hours. The catalyst is removed by filtration, and the filtrate is evaporated to obtain 0.75 g (94 %) of the title compound. M.p.: 11 1-114 °C. Analysis for C 3H2-| F3θ3 calculated: C 68.65 %, H 5.26 %; found: C 68.22 %, H 5.10 %.
1 H-NMR (250 MHz, CDCl3) ppm: 7.59 (d, 2H, J 8.9 Hz); 7.5-6.9 (m, 10H); 6.89 (d, 2H, J 8.9 Hz); 4.58 (q, 1 H, JH F 9.2 Hz); 4.1 -4.0 (m, 2H); 4.0-3.9 (m, 2H); 2.92 (s, 1 H); 2.15 (bs, 1 H).
Example 22 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-hydroxyethoxy)- phenyl]propene
5.0 g (10.3 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1- hydroxy-3,3,3-trifluoro-1-{4-[2-(2-tetrahydropyranyloxy)- q ethoxy]phenyl}propane are boiled in a mixture of 50 cm° of ethanol and 10 cm3 of concentrated hydrochloric acid for 30 minutes. The reaction mixture is poured onto 100 cm3 of water, and extracted 3 times with 50 cm3 of dichloromethane each time. The organic layers are combined, washed with 30 cm3 of water, and evaporated. The residual oil is dissolved in 90 cm3 of n-hexane, and the solution obtained is cooled to 0 °C to crystallize the product. The crude product contains about 9 % of (Z) isomer. When recrystallized from 180 cm3 of n-hexane, the content of (Z) isomer becomes lower than 2 %. 3.0 g (75 %) of the title compound are obtained. M.p.: 1 18-1 19 °C. Analysis for C23H1 9F3θ2 calculated: C 71.87 %, H 4.98 % F 14.83 %; found: C 71 ,91 %, H 4.94 % F 15.12 %.
"Η-NMR (250 MHz, CDCI3) ppm: 7.45-7.1 (m, 10H); 6.81 (d, 2H, J 8.8 Hz); 6.55 (d, 2H, J 8.8 Hz); 3.95-3.75 (m, 4H); 2.06 (bs, 1 H).
Example 23 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-hydroxyethoxy)- phenyl.propene
5.0 g (1 1 .2 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1 - -hydroxy-3,3,3-trifluoro-1-[4-(2-methoxymethoxyethoxy)- q phenyl.propane are boiled in a mixture of 50 c J of ethanol and 10 cm3 of concentrated hydrochloric acid for q
1 .5 hours. The reaction mixture is poured onto 100 crrr of water, and extracted 3 times with 50 cm3 of dichloro¬ methane each time. The organic layers are combined, washed with 30 cm3 of water, and evaporated. The residual 4.2 g of crude product containing about 1 1 per q cent of the (Z) isomer are recrystallized from 250 cm° of n-hexane to obtain 3.5 g (82 %) of the title compound containing about 3 per cent of the (Z) isomer. M.p. 1 19-120 °C.
Example 24 1 ,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-hydroxyethoxy)- phenyljpropene
0.40 g (0.8 mmoles) of 1 ,2-diphenyl-3,3,3-trifluoro-1 - -[4-(2-benzyloxyethoxy)phenyl]propene having an (E)/(Z) isomeric ratio of 7.3:1 are hydrogenized in 10 cm3 of ethanol in the presence of 0.1 g of 10 % palladium/carbon catalyst at atmospheric pressure and at the boiling point of the solvent for 4 hours. The catalyst is filtered, and the filtrate is evaporated to obtain 0.76 g (94 %) of the title compound. The ratio of the (E)/(Z) isomers = 7.3:1.
Example 25 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -[N- -benzyl-N-(2-benzyloxyethyl)-4-(2-aminoethoxy)phenyl]- propane
To a dry flask containing 0.19 g (7.8 mmoles) of magnesium cuttings, a small crystal of iodine, then a solution of 3.52 g (8.0 mmoles) of N-benzyl-N-(2-benzyl- oxyethyl)-4-(2-aminoethoxy)bromobenzene in 8 cm3 of anhydrous tetrahydrofuran are added. After the addition of 0.05 g of carbon tetrachloride, the reaction mixture is boiled under nitrogen for 4 hours. After 2.5 hours, the mixture becomes darker yellow and begins to opalesce. At the end of the boiling period, the chief part of magnesium is dissolved. To the solution of the Grignard's reagent cooled to 25 °C, a solution of 0.70 g (2.7 mmoles) of 2- -phenyl-3,3,3-trifluoropropiophenone in 3 cm° of anhydrous tetrahydrofuran is added. The reaction mixture is left to stand for a night, then, poured onto 40 cm3 of 0.5 M aqueous ammonium chloride solution, extracted 4 times with 20 cm3 of dichloromethane each time, the q organic layers are combined, washed with 20 cm° of water, and evaporated. The residue is transferred to a column filled with Kieselgel 60, and eluted with a mixture of toluene and ethyl acetate (95:5). 0.92 g (55 %) of title compound are obtained. Analysis for C39H38F3NO3 (625.7) calculated: C 74.86 %, H 6.12 % N 2.24 %; found: C 74,74 %, H 6.19 % N 2.27 %.
1 H-NMR (250 MHz, CDCl3) ppm: 7.53 (d, 2H, J 8.9 Hz); 7.4-6.9 (m, 20H); 6.82 (d, 2H, J 8.9 Hz); 4.57 (q, 1 H, JH F 9.2 Hz); 4.48 (s, 2H); 4.00 (t, 2H, J 6.1 Hz); 3.77 (s, 2H); 3.59 (t, 2H, J 5.9 Hz); 2,95 (t, 2H, J 6.1 Hz); 2.86 (t, 2H, J 5.9 Hz); 2.80 (s, 1 H).
Example 26 1 ,2-Diphenyl-3,3,3-triflυoro-1-[N-benzyl-N-(2-benzyloxy- ethyl)-4-(2-aminoethoxy)phenyl]propene
1.82 g (2.9 mmoles) of 1RS,2RS-1 ,2-diphenyl-1- -hydroxy-3,3,3-trifluoro-1-[N-benzyl-N-(2-benzyloxyethyl)- -4-(2-aminoethoxy)phenyl]propane are dissolved in 35 cm3 of ethanol, 7 cm3 of concentrated hydrochloric acid are added, and the mixture is boiled under reflux for 2 hours. q
The reaction mixture is cooled, poured onto 70 cm of water, and extracted 3 times with 35 cm3 of dichloro¬ methane each time. The organic layers are combined, washed twice with 20 cm3 of water each time, and evaporated. The residue is transferred to a column filled with Kieselgel 60, and eluted with a mixture of toluene and methanol (8:2). 1.17 g (66 %) of the title compound are obtained. The ratio of (E)/(Z) isomers = 5.5:1. 1 H-NMR (250 MHz, CDCI3) ppm: 7.4-7.15 (m, E 20H + Z 17H); 7.05-6.85 (m, Z 7H); 6.77 (d, E 2H, J 8.8 Hz); 6.47 (d, E 2H, J 8.8 Hz); 4.49 (s, Z 2H); 4.44 (s, E 2H); 4.04 (t, Z 2H J 6.1 Hz); 3.85 (t, E 2H, J 6.1 Hz); 3,79 (s, Z 2H); 3.70 (s, E 2H); 3,61 (t, 2H, J 5.9 Hz); 3.53 (t, E 2H, J 5.9 Hz); 2.98 (t, Z 2H, J 6.1 Hz); 2.86 (t, E 2H, J 6.1 Hz); 2.8-2.7 (m, E 2H + Z 2H). Example 27 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1 -{4-[2-(2-hydroxyethyl- amino)ethoxy]phenyl}propene (panomifen)
1.5 g (2.5 mmoles) of 1 ,2-diphenyl-3,3,3-trifluoro-1- -[N-benzyl-N-(2-benzyloxyethyl)-4-(2-aminoethoxy)phenyl]- -propene having an (E)/(Z) isomeric ratio of 5.5:1 are dissolved in 60 cm3 of ethanol at 25 °C, then 0.3 g of 10 per cent palladium/carbon catalyst and 2.5 cm3 of concentrated hydrochloric acid are added, and the mixture is hydrogenized for 4.5 hours under stirring. The catalyst is removed by filtration, and the filtrate is evaporated. The residual hydrochloride is treated with 5 per cent aqueous sodium hydrogen carbonate solution to obtain the free base that is extracted 3 times with 40 cm3 of chloroform each time, the organic layers are combined, dried over anhydrous magnesium sulfate, and evaporated. The q residue is treated with 20 cm° of n-hexane to obtain 0.68 g (64 %) of the title compound. M.p.: 96-98 °C (ethyl acetate). M.p. in GB-P 2 058 061 is equivalent to 96-98 °C.
Example 28 (E)-1 ,2-Diphenyl-3,3,3-trifluoro-1 -{4-[2-(2-hydroxyethyl- amino)ethoxy]phenyl}propene (panomifen)
A mixture of 0.84 g (2.0 mmoles) of 1 RS,2SR-1 ,2- -diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -[4-(2-chloroethoxy)- phenyllpropane, 1.2 g (20 mmoles) of 2-aminoethanol and 8 cm3 of 2-methoxyethanol is boiled for one hour. 4 cm3 of concentrated hydrochloric acid are added to the reaction mixture that is boiled for further 30 minutes to perform dehydration. The cooled mixture is poured onto 80 cm3 of saturated aqueous sodium hydrogen carbonate solution, then 40 cm3 of water are added, and the mixture obtained is extracted 3 times with 40 cm3 of dichloromethane each time. The organic layers are combined, washed with 40 q crrr of water, and evaporated. The residue is transferred to a column filled with Kieselgel 60, and eluted with a mixture of toluene and methanol (4:1 ). The product containing about 20 per cent of the (Z) isomer is recrystallized from isopropanol to reduce the content of the (Z) isomer to about 2 per cent. In this way, 0.10 g (14 %) of the title compound are obtained. M.p.: 95-97 °C.
Example 29 1 ,2-Diphenyl-3,3,3-trifluoro-1-{4-[2-(2-hydroxyethylamino)- -ethoxy]phenyl}propene
A mixture of 0.40 g (0.9 mmoles) of 1 RS,2RS-1 ,2- -diphenyl-1 -hydroxy-3,3,3-trifluoro-1-{4-[2-(2-hydroxy- ethylamino)ethoxy]phenyl}propane, 10 cm3 of ethanol and 2 cm3 of concentrated hydrochloric acid is boiled for one hour, then poured onto an excess of aqueous sodium hydrogen carbonate solution, and extracted twice with 40 cm3 of dichloromethane each time. The organic layers are combined, washed with 40 cm3 of water, and evaporated to obtain 0.28 g (73 %) of the title compound. The isomeric ratio (E)/(Z) = 5.9:1.
Example 30 1 RS,2RS-1 ,2-Diphenyl-1-hydroxy-3,3,3-trifluoro-1 -[4-(2- -tetrahydropyranyloxy)phenyl]propane
A mixture of 22.8 g (94 mmoles) of 4-(2-tetrahydro- pyranyloxy)bromobenzene, 2.28 g (94 mmoles) of q magnesium cuttings and 94 cm° of anhydrous tetrahydrofurane are boiled for one hour to yield the Grignard's reagent. To the mixture cooled to 20 °C, a solution of 8.3 g (31 mmoles) of 2-phenyl-3,3,3-trifluoro- propiophenone in 30 cm3 of anhydrous tetrahydrofuran is added while maintaining the temperature at 20 to 25 °C. The reaction mixture is stirred at 25 °C for one hour, then poured onto 450 cm3 of 0.5 M aqueous ammonium chloride solution at 10 °C, and extracted twice with 200 q cmJ of dichloromethane each time. The organic layers are combined, washed with 200 cm3 of water, and evaporated. The residual oil is transferred to a column filled with Kieselgel 60, and eluted with toluene, then recrystallized from isopropanol to obtain 3.17 g (23 %) of title compound. M.p.: 152-153 °C. Analysis for C26H25F3O3 (442.49) calculated: C 70.58 %, H 5.69 %; found: C 70,65 %, H 5.67 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.58 (d, 2H, J 9 Hz); 7.4-6.9 (m, 14H); 5.39 (t, 1 H, J 2.9 Hz); 4.59 (q, 1 H, JH F 9.2 Hz); 4.0-3.8 (m, 1 H); 3.65-3.5 (m, 1 H); 2.83 (s, 1 H); 2.1-1.5 (m, 6H).
Example 31 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -{4-[2-(2- -hydroxyethylamino)ethoxy]phenyl}propane
0.55 g (0.9 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1 - -hydroxy-3,3,3-trifluoro-1 -[N-benzyl-N-(2-benzyloxyethyl)- -4-(2-aminoethoxy)phenyl]propane are hydrogenized in 5 cm3 of ethanol in the presence of 0.1 g of 10 per cent palladium/carbon catalyst for 20 hours at atmospheric pressure and at the boiling point of the solvent. After the removal of the catalyst by filtration, the filtrate is evaporated. The residue is transferred to a column filled with Kieselgel 60, and eluted with a mixture of toluene and methanol (4:1 ). 0.23 g (59 %) of the title compound are obtained. M.p.: 121-123 °C. Analysis for C 5H26F3NO3 (445.49) calculated: C 67.40 %, H 5.88 % N 3.14 %; found: C 66,90 %, H 5.97 % N 3.02 %.
1 H-NMR (250 MHz, CDCI3) ppm: 7.57 (d, 2H, J 8.8 Hz); 7.4-6.8 (m, 12H); 4.57 (q, 1 H, JH F 9.2 Hz); 4.00 (t, 2H J 5.0 Hz); 3.64 (t, 2H J 5.1 Hz); 2.97 (t, 2H, J 5.0 Hz); 2.81 (t, 2H, J 5.1 Hz); 2.6 (bs,1 H).
Example 32 1 RS,2RS-1 ,2-Diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -(4- -hydroxyphenyDpropane
2.00 g (4.5 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1 - -hydroxy-3,3,3-trifluoro-1 -[4-(2-tetrahydropyranyl- oxy)phenyl]propane are dissolved in 100 cm3 of ethanol, and, to the solution obtained, 10 cm3 of concentrated hydrochloric acid are added while maintaining the temperature below 25 °C. The mixture is left to stand for 30 minutes at room temperature, then poured onto 200 cm3 of water, and extracted twice with 100 cm3 of dichloromethane each time. The organic layers are combined, washed twice with 50 cm3 of water each time, and evaporated. The residual oil is boiled with 15 cm3 of n-hexane for 30 minutes, and the product is filtered to obtain 1.55 g (96 %) of the title compound. M.p.: 1 17-119 °C. Analysis for C H1 7F3O2 (358.37) calculated: C 70.38 %, H 4.78 %; found: C 70.66 %, H 4.95 %.
"Η-NMR (250 MHz, CDCI3) ppm: 7.53 (d, 2H, J 8.8 Hz); 7.4-6.9 (m, 10H); 6.79 (d, 2H, J 8.8.); 4.88 (s, 1 H); 4.57 (q, 1 H, JH F 9.2 Hz); 2.81 (s,1 H).
Example 33 1 ,2-Diphenyl-3,3,3-trifluoro-1 -(4-hydroxyphenyl)propene 1.00 g (2.8 mmoles) of 1 RS,2RS-1 ,2-diphenyl-1- -hydroxy-3,3,3-trif luoro-1 -(4-hydroxyphenyl)propane is dissolved in 10 cm3 of. ethanol, and 2 cm3 of concentrated hydrochloric acid are added, drop by drop, while maintaining the temperature below 25 °C. The reaction mixture is left to stand at room temperature for 2 days, then poured onto 25 cm3 of water, filtered at 0 °C, and washed with water. In this way, 0.91 g (96 %) of the title compound are obtained. The isomeric ratio (E)/(Z) = 3.3:1 .
1 H-NMR (250 MHz, CDCI3) ppm: 7.4-7.15 (m, E 10H + Z 7H); 7.1-7.0 (m, Z 3H); 6.95-6.85 (m, Z 2H); 6.85-6.7 (m, E 2H + Z 2H); 6.46 (d, E 2H, J 8.7 Hz); 4.9 (bs, Z 1 H); 4.7 (bs, E 1 H).
Example 34 1 ,2-Diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene
0.20 g (0.5 mmoles) of 1RS,2RS- or 1 RS,2SR-1 ,2- -diphenyl-1 -hydroxy-3,3,3-trifluoro-1 -(4-methoxymethoxy- phenyUpropane are dissolved in 8 cm3 of ethanol, and, to the solution obtained, 1 cm3 of concentrated hydrochloric acid are added, drop by drop, while maintaining the temperature below 25 °C. The reaction mixture is left to stand for 2 days at room temperature, then poured onto 20 cm3 of water, and extracted twice with 10 cm3 of dichloromethane each time. The organic layers are combined, washed twice with 5 cm3 of water each time, and evaporated to yield 0.16 g (95 %) of the title compound. The isomeric ratio (E)/(Z) = 2.7:1 .
Example 35 1 ,2-Diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)propene
0.30 g (0.8 mmoles) of 1RS,2RS- or 1 RS,2SR-1 ,2-di- phenyl-1-hydroxy-3,3,3-trifluoro-1-(4-methoxyphenyl)- 45
propane are heated in the melt of 1.2 g of pyridinium chloride at 210 °C for one hour. To the mixture cooled, 15 cm3 of 2 N hydrochloric acid are poured, and the mixture obtained is extracted twice with 15 cm3 of chloroform each time. The organic layers are combined, evaporated, the residue is transferred to a column filled with Kieselgel 60 , and eluted with toluene to obtain 0.07 g (26 %) of the title compound. The isomeric ratio (E)/(Z) = 1 :1.

Claims

Claims: 1. A process for preparing triphenyltrifluoropropanes and -propenes of the formula
Figure imgf000048_0001
wherein
R<1 represents hydrogen, R stands for hydroxy, or R<I forms together with R a valence bond, B is hydrogen, methyl, methoxymethyl, tetrahydro¬ pyranyl or a group of the formula
Figure imgf000048_0002
wherein R3 represents a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula
R4-O-CH2-CH2-N-R4 b
wherein R4 stands for hydrogen or benzyl, as well as possible optical isomers or geometrical isomers and mixtures thereof, in which a) for the preparation of hydroxypropane derivatives of the formula
Figure imgf000049_0001
being a sub-group of the compounds of the formula III, wherein in formula II B stands for methyl, methoxymethyl, tetrahydropyranyl or a group of the formula a wherein R3 represents a halo, benzyloxy, methoxymethoxy, tetra¬ hydropyranyloxy or a group of the formula b wherein R4 is benzyl, a propiophenone derivative of the formula
V
Figure imgf000049_0002
wherein A represents hydrogen, is reacted with a bromobenzene of the formula
Figure imgf000050_0001
wherein B is as stated above, under the conditions of the Grignard's reaction; or b) for the preparation of hydroxypropane derivatives of the formula II being a sub-group of the compounds of the formula III wherein in formula II B represents methyl, methoxymethyl or a group of the formula a wherein R3 stands for a halo, a propiophenone derivative of the formula V wherein A represents methoxy, methoxy¬ methoxy, tetrahydropyranyloxy or a group of the formula
O-CH2-CH2-R5 c
wherein R5 is a halo or benzyloxy, is reacted with bromo¬ benzene under the conditions of the Grignard's reaction; and, if desired, a compound of the formula II obtained is transformed into another compound of the formula II within the definition of B given in relation to formula III in a manner known per se. and/or a compound of the formula II is dehydrated with an acid to obtain a propene derivative of the formula
Figure imgf000051_0001
wherein B is as defined in relation to formula III, and, if desired, the compound of the formula I is transformed into another compound of the formula I within the definition of B in a manner known per se.
2. Triphenyltrifluoropropanes and -propenes of the formula
Figure imgf000051_0002
wherein R-j is hydrogen, R represents hydroxy, and
B stands for hydrogen, methyl, methoxymethyl, tetra¬ hydropyranyl or a group of the formula
-CH2-CH -Rq
wherein R3 represents a halo, hydroxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula
R -O-CH2-CH2-N-R4 b
wherein R4 stands for hydrogen or benzyl, or R-j forms together with R a valence bond, and B stands for tetrahydropyranyl or a group of the formula wherein R3 is hydroxy, benzyloxy, methoxy¬ methoxy, tetrahydropyranyloxy or a group of the formula b wherein R4 is benzyl, as well as possible optical isomers or geometrical isomers or mixtures thereof.
3. Hydroxypropane derivatives of the formula
Figure imgf000052_0001
wherein
B stands for hydrogen, methyl, methoxymethyl, tetra¬ hydropyranyl or a- group of the formula a wherein R3 denotes a halo, hydroxy, benzyloxy, methoxy¬ methoxy, tetrahγdropyranyloxy or a group of the formula h_ wherein R4 is hydrogen or benzyl, as well as optical isomers and mixtures thereof.
4. Propene derivatives of the formula
Figure imgf000053_0001
wherein
B stands for tetrahydropyranyl or a group of the formula a wherein R3 represents hydroxy, benzyloxy, methoxymethoxy or tetrahydropyranyloxy, as well as geometrical isomers and mixtures thereof.
5. 2-Phenyl-3,3,3-trifluoropropiophenone derivatives of the formula
V
Figure imgf000053_0002
wherein
A represents hydrogen, hydroxy, methoxy, benzyloxy, methoxymethoxy, tetrahydropyranyloxy or a group of the formula
-O-CH2-CH2-R d
wherein R denotes a halo, hydroxy or benzyloxy, as well as optical isomers and mixtures thereof.
PCT/HU1995/000056 1994-11-02 1995-11-02 Process and intermediates for preparing triphenyltrifluoropropanes and -propenes WO1996014283A1 (en)

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WO1999002509A1 (en) * 1997-07-07 1999-01-21 Smithkline Beecham Plc Process for preparing tri-aryl-alkylalkenes

Citations (2)

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Publication number Priority date Publication date Assignee Title
US3712929A (en) * 1969-10-31 1973-01-23 Du Pont 1-perfluoroalkyl-1,2,2-triphenylethylenes
GB2058061A (en) * 1979-08-15 1981-04-08 Egyt Gyogyszervegyeszeti Gyar 1,1,2-Triphenylpropane and -propene derivatives

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US3712929A (en) * 1969-10-31 1973-01-23 Du Pont 1-perfluoroalkyl-1,2,2-triphenylethylenes
GB2058061A (en) * 1979-08-15 1981-04-08 Egyt Gyogyszervegyeszeti Gyar 1,1,2-Triphenylpropane and -propene derivatives

Non-Patent Citations (1)

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Title
IN HOWA JEONG ET AL: "A new method for the preparation of alpha-fluorinated and alpha-perfluoroalkylated ketones", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 15, no. 1, 20 January 1994 (1994-01-20), pages 1 - 3 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002509A1 (en) * 1997-07-07 1999-01-21 Smithkline Beecham Plc Process for preparing tri-aryl-alkylalkenes

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