PROCESS FOR PREPARING 4-HYDROXYCOUMARIN DERIVATIVES

Abstract: The invention provides a process for preparing a 4-hydroxycoumarin derivative having anti-coagulant prop­ erties, useful as a rodenticide, of formula wherein R¹ and R² are independently selected from the group consisting of hydrogen, halogen, alkyl of up to 6 carbon atoms and alkoxy of up to 6 carbon atoms, and R³ represents a group selected from where X represents a halogen atom or a group C₁ ₁₂ alkyl, C₁ ₁₂ alkoxy, C₃₋₈ cycloalkyl, CN, SO₂R⁵, CF₃, OCF₃, COOR⁵ or COR⁵, where R⁵ is C₁ ₆ alkyl, n′ is 0, 1 or 2 and Y is a fluorine or chlorine atom; where n′ and Y are as defined above, X is as defined above or is hydrogen, n″ is 0 or 1 and D is an oxygen atom or a group -O-(CH₂) m -, -(CH₂) m -O-, -O-(CH₂) m -O-(CH₂) p -, -(CH₂)- m , or -CH=CH-, or a sulphur ana logue thereof, wherein m is in the range 1 to 6 and p is in the range 1 to 6; where X, n′ and Y are as defined in (a) above. (d) a group selected from and and (e) a group selected from where X and n″ are defined as in (b) above, A is an oxygen or sulphur atom and D′ is an oxygen atom or a -CH₂- group, which process comprises condensing 4-hydroxycoumarin with a compound of formula or the corresponding 1,2-dihydronaphthalene, wherein R¹, R² and R³ are as defined above, and L is a hydroxy group or a halogen aotm, in the presence of an organic solvent and a catalyst characterised in that the solvent is selected from formic acid, a mixture of formic acid and at least one C₂₋₆ aliphatic acid having a boiling temperature at atmospheric pressure in the range 60°C to 105°C and a liquid halogenated hydrocarbon having a boiling temperature of at least 60°C, and reaction is effected at a temperature in the range 60°C to the reflux temperature of the reaction mixture.

Description: PROCESS FOR PREPARING 4-HYDROXYCOUMARIN DERIVATIVES This invention relates to a process for preparing certain 4-hydroxycoumarin derivatives. US Patent No. 3,957,824 (and the corresponding UK Patent Specification No. 1,458,670) discloses a class of 4-hydroxycoumarin derivatives having anti-coagulant properties, which are useful as rodenticides or in human medicine, of general formula EMI1.1 where R1 and 2 are the same or different and are hydrogen or halogen atoms, preferably chlorine or bromine, or alkyl or alkoxy groups, preferably having up to 6 carbon atoms, R is an arvi group having the formula EMI1.2 where m is 1 or 2, and R is the same or different and is a halogen atan, a straight or branched chain alkyl or alkoxy group, preferably containing at least 2, more preferably from 5 to 12 carbon atans, a cycloalkyl, preferably cyclohexyl group, an aralkyl, preferably &alpha; -aralkyl group, a phenyl or a phenoxy group, or a halogeno, preferably para halogeno, substituted derivative thereof. The halogen atan or atoms are preferably chlorine or bromine. Where m is 1, R is preferably in the para position and when m is 2 one of the R groups is preferably in the para position. Preferably R3 contains at least 1 but not store than 3 and optimally not more than 2 halogen atans. The above compounds of fornula I are prepared by condensing 4-hydroxy coumarin (II) with compounds of general formula III without a solvent or in an organic solvent such as acetic acid in the presence of a dehydrating agent such as sulphuric acid or by condensing 4-hydroxy cournarin (11) with a campund of general formula IV with or without the use of a solvent, EMI2.1 R1, R2 and R3 have the meanings given previously and Hal is halogen, preferably chlorine or branine. Ccmpounds of structure IV may be prepared from compounds of general structure III by treatment with reagents such as phosphorus tribranide, phosphorus trichloride or thionyl chloride in an inert solvent such such as methylene chloride, chloroform or carbon tetrachloride. The lowest temperature employed in such a preparation is in condensation of such compounds of fo=milae II and III in acetic acid at 1100C. When no solvent is present, condensation of compounds of formulate II and III is typically effected at 160 to 1700C. Reaction of catponds of formulae II and IV is typically at 130 to 1400C (for these latter temperature ranges see Shadbolt et al J.C.S. Perkin 1, (1976) No. 11, pages 1190 to 1195). Two specific compounds of formula I above are that wherein R1 and R2 are both hydrogen and R3 is a 4-phenyiphenyl group (difenaccum) and that wherein R1 and R2 are both hydrogen and R3 is a 4- (4-bratcyl)phenyl group (brodifacoum). GB-A-2 126 578, and the corresponding EP-A-98 629, discloses a further class of 4-hydroxycoumarin derivatives having anticoagulant properties, particularly as rodenticides. In their broadest definition, these caaonds have the formula EMI3.1 in which Z represents a halogen atcm, preferably a chlorine atan, and n is 0, 1 or 2 and R4 represents either (1) a grouping which comprises a phenylene radical attached directly or indirectly to the tetralin ring and having in the para position (with respect to such attachment an electron-withdrawing atan or group whose rotational volume substantially @ does s not exceed that of a phenyl group and which forms together with said phenylene radical a polarisable structure, or (2) a grouping selected from: : EMI4.1 or (3) a grouping wL' ch ccmprises a phenylene radical attached directly to the tetralin ring and having in the para position (with respect to such attachment) a substituted furanyl or thiophenyl radical attached thereto directly or through oxygen and/or methylene, said furanyl or thiophenyl radical having an electron-withdrawing atan or group as a substituent in a position forming with the furanyl or thiophenyl radical a polarisable structure, said atan or group having a rotational volume which substantially does not exceed that of a phenyl group. In the above formula V, R4 is preferably more specifically defined as a group selected frcm EMI4.2 where X represents a halogen atom or a group CN, NO2, SO2R5, CF3, OCF3, COOR5 or COR5, where R5 is a C1-6 alkyl group, n' is 0, 1 or 2 and Y is a fluorine or chlorine atom, provided that when X is halogen, n' is 1 or 2; EMI4.3 where X, n' and Y are as defined above, n" is 0 or 1 and D is an oxyen atom or a group -O-(CH2)m-, -(CH2)m-O-, -O-(CH2)m-O-, -(CH2)m-O-(CH2)p-, -(CH2)-m, or -CH=CH-, or a sulphur analogue thereof, wherein m is in the range 1 to 6 and p is in the range 1 to 6, provided that when D is an oxygen atcm and X is halogen, n' is 1 or 2, and when D is -CH=CH-, X may additionally be a hydrogen atom; ; EMI5.1 where X, n' and Y are as defined above, (d) a group selected fran EMI5.2 EMI5.3 (e) a group selected fran EMI5.4 where X and n" are as defined above, A is an oxygen or sulphur atan and D' is an oxygen atcm or a -CH2- group. The compounds of formula V above are prepared by processes directly analogous to those described for compounds of formula I above (e.g. in US Patent No. 3,957,824 and Shadbolt et al J.C.S. Perkin 1, (1976) No. 11, pages 1190 to 1195). It has now surprisingly been found possible that compounds of the above formulae I and V may be prepared in enhanced yield and at temperatures below those heretofore employed. According to the present invention there is provided a process for preparing a 4-hydroxy coumarin derivative of formula EMI6.1 wherein R1 and R2 are independently selected fran the group consisting of hydrogen, halogen, alkyl of up to 6 carbon atoms and alkoxy of up to 6 carbon atoms, and R3 represents a group selected fran EMI6.2 where X represents a halogen atcm or a group C1-12 alkyl, C1-12 alkoxy, C3-8 cycloalkyl, CN, SO2R5, CF3, OCF3, COOR or where R5 is C1-6 alkyl, n' is 0, 1 or 2 and Y is a fluorine or chlorine atan; ; EMI6.3 where n' and Y are as defined above, X is as defined above or is hydrogen, n" is 0 or 1 and D is an oxygen atom or a group O-(CH2)m-, -(CH2)m-O-, -O-(CH2)m-O-, -(CH2)m-O-(CH2)p-, (CH2)-m, or -CH=CH-, or a sulphur analogue thereof, wherein m is in the range 1 to 6 and p is in the range 1 to 6; EMI6.4 where X, n' and Y are as defined in (a) above: : (d) a group selected from EMI7.1 EMI7.2 (e) a group selected frDm EMI7.3 where X and n" are as defined in (b) above, A is an oxygen or sulphur atan and D' is an oxygen atan or a -CH2- group, which process comprises condensing 4-hydroxycoumerin with a compound of formula EMI7.4 or the corresponding 1,2-dihydronaphthalene, wherein R1, R2 and R3 are as defined above, and L is a hydroxy group or a halogen atom, in the presence of an organic solvent and a catalyst characterised in that the solvent is selected fran formic acid, a mixture of formic acid and at least one C2-6 aliphatic acid having a boiling temperature at atrrDspheric pressure in the range 60 C to 1050C and a liquid halogenated hydrocarbon having a boiling temperature of at least 600C, and reaction is effected at a temperature in the range 60 C to the reflux temperature of the reaction mixture. L in formula VI is preferably OH, Br or Cl. Preferably in formula VI, R1 and R2 are both hydrogen. When X is not hydrogen it preferably represents a fluorine, chlorine or branine atan or a group CN, NO2, CF3 or OCF3, more preferably a chlorine or branine atan or a group CN or CF3. 3 R preferably has the fornula EMI8.1 and it is preferred for D to be an oxygen atan, a group -CH2-CH2-, -CH2-CH2-CH2- or -CH=CH-. It is further preferred that n' is 0, n" is 0 or 1, D is an oxygen atom or a group O-CH2- and X is a group CF3, H, CN or Br. The process of the invention id of most particular interest when applied to the preparation of difenacoum, brodifacoum or 3-[3-{4-(4-trifluoromethylbenzyloxy)phenyl)-1,2,3,4-tetrahydro1-naphthyl]-4-hydroxycoumarin. The e organic solvent may be formic acid or a mixture of formic acid and at least one C2¯6 6 aliphatic carboxylic acid having a boiling temperature at atmospheric pressure in the range 600C to 1050C . Mixtures of formic acid (boiling temperature 100.50C) and glacial acetic acid (boiling temperature 1180C) having boiling temperatures in this range, particularly in volume proportions formic acid: acetic acid of about 3:1, are preferred. With such solvents the catalyst may conveniently be a mineral acid, such as sulphuric or, preferably, orthophosphoric acid; an acid salt, such a potassium hydrogen sulphate; a lexis acid such as ferric chloride, zinc chloride or potassium chloride; or silica gel. Reaction temperatures in such solvent/catalyst systems are preferably in the range 70 C to reflux temperature, more preferably 800C to reflux temperature. In a preferred process of the invention, the solvent is a liquid halogenated hydrocarbon, preferably a halogenated alknne, having a boiling temperature at atmospheric pressure of at least 600C, the catalyst is a sulphonic acid, and reaction is effected at a temperature in the range 600C to the reflux temperature of the reaction mixture. The halogenated hydrocarbon is one which is liquid at ambient temperature. Liquid chlorinated alkanes, e.g. C2-4 diand trichloroalkanes , are very suitable. Examples of such chlorinated alkanes include 1,2-dichloroethane (b.p. 83 C to 840C), 1,1,2-trichloroethane (b.p. 113 C to 114 C), 1,1,1-trichloroethane (b.p. 74 C to 75 C), 1,1-dichloropropane (b.p. 87 C), 1,2-dichloropropane (b.p. 950C to 960C) and 1,3-aichioropropane (b.p. 125 C). Other such halogenated hydrocarbons will be immediately apparent to those skilled in the art. 1,2-Dichloroethane, 1,1, 2-trichloroethane and 1,3-dichloropropane have been found to be very suitable. Examples of sulpoonic acids include methanesulphonic acid, trifluoromethanesulphonic acid, and aryl sulphonic acids such as benzenesulphonic acid and P-toluenesulphonic acid. In processes of the invention, the relative quantities of the reactants are not critical. However it is preferred for there to be 1 to 4 idols, preferably 1 to 3 mols, of 4-hydrxycomarin per mol of compound of formula VI, and, in the case of a sulphonic acid catalyst, for there to be 0.25 to 2 tools, preferably 0.5 to 1.5 mols, of sulphonic acid per mol of compound of formula VI. The invention will be further understood fran the following Examples. Example 1 3-(4-(4-Trifluoromethylbenzyloxy)phenyl)-1,2,3,4-tetrahydro-1- naphthol (8g, 0.02M), 4-hydroxycoumarin (6.5g, 0.04M) and p-toluenesulphonic acid (1.9g, 0.01M) were refluxed in 1,2-aichioroethane (80ml) in a Dean-Stark apparatus under nitrogen, for 24 hours (boiling point of dichloroethane 83-84 C). The resulting solution was then cooled, washed with water and evaporated to yield a solid residue which was purified by chromatography on silica gel using dichloromethane as eluant to give 3-[3-(4-trifluoromethylbenzyloxy)phenyl)-1,2,3,4tetrahydro-1-naphthyl]-4-hydroxycoumarin (9,9g, 90%) m.p. 85-86 C. Example 2 1-Chloro-3-(4-(4-trifluoromethylbenzyloxy)phenyl)-1,2,3,4tetrahydronaphthalene (2.08g, 0.005M) and 4-hydroxycoumarin (2.49g, 0.0 15M) were added to a mixture of formic acid and glacial acetic acid (3:1 v/v; aml) containing orthophosphoric acid (100mg). The mixture was refluxed with stirring under nitrogen, for 3 hours. The resulting mixture was cooled and diluted with dichloromethane to give a solution which was washed with water. Evaporation of the dichloromethane solution gave a solid residue which was purified by chromatography on silica gel using dichloratethane as eluant to give 3-[3-(4-(4-trifluoromethylbenzyloxy)phenyl)-1,2,3,4-tetrahydro-1-naphthyl]-4-hydroxycoumarin (1.6g, 60%) m.p. 85-860C. Examples 3 to 14 3-[3-(4-(4-Trifluoromethylbenzyloxy)phenyl)-1,2,3,4tetrahydro-1-naphthyl]-4-hydroxycoumarin was prepared by process variants of Example 1, the volume of solvent in Examples 8 to 14 being higher (130 ml). The variants and the yields are given in Table I following, in which S.M. stands for starting material, "hydroxy" being the naphthol derivative used in Example 1 and "chloro" being the 1-chloronaphthalene derivative used in Example 2, pTSk is p-toluenesulphonic acid, BSA is benzenesulphonic acid, MSA is methanesulphonic acid, DCE is 1,2-dichloroethane (b.p. 83-84 C), TCE is 1,1,2-trichlorethane (b.p. 113-1140C) and DCP is 1,3-dichIoropropane (b.p. 1250C). Table I EMI11.1 Example <SEP> S.M. <SEP> Reaction <SEP> Reaction <SEP> Mois <SEP> 4-hydroxycoumarin <SEP> Sulphonic <SEP> acid <SEP> Solvent <SEP> Yield <tb> <SEP> (Mols <SEP> acid <SEP> per <tb> <SEP> Temperature <SEP> Time <SEP> (hours) <SEP> per <SEP> mol <SEP> S.M. <SEP> mol. <SEP> S.M.) <tb> <SEP> 3 <SEP> hydroxy <SEP> reflux <SEP> 22 <SEP> 3 <SEP> pTSA <SEP> (1) <SEP> DCE <SEP> 87 <tb> <SEP> 4 <SEP> chloro <SEP> reflux <SEP> 24 <SEP> 3 <SEP> pTSA <SEP> (1) <SEP> DCE <SEP> 74 <tb> <SEP> 5 <SEP> hydroxy <SEP> reflux <SEP> 24 <SEP> 3 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 82 <tb> <SEP> 6 <SEP> hydroxy <SEP> reflux <SEP> 24 <SEP> 3 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 82 <tb> <SEP> 7 <SEP> hydroxy <SEP> reflux <SEP> 24 <SEP> 3 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 87 <tb> <SEP> 8 <SEP> hydroxy <SEP> reflux <SEP> 26 <SEP> 1 <SEP> 05 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 88 <tb> <SEP> 9 <SEP> hydroxy <SEP> reflux <SEP> 25 <SEP> 2 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 92.25 <tb> <SEP> 10 <SEP> hydroxy <SEP> reflux <SEP> 25 <SEP> 1 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 90 <tb> <SEP> 11 <SEP> hydroxy <SEP> reflux <SEP> 26 <SEP> 2 <SEP> pTSA <SEP> (0.5) <SEP> DCE <SEP> 90 <tb> <SEP> 12 <SEP> hydroxy <SEP> reflux <SEP> 26 <SEP> 2 <SEP> pTSA <SEP> (0.5) <SEP> DCP <SEP> 90 <tb> <SEP> 13 <SEP> hydroxy <SEP> reflux <SEP> 24 <SEP> 2 <SEP> MSA <SEP> (0.5) <SEP> DCE <SEP> 92 <tb> <SEP> 14 <SEP> hydroxy <SEP> reflux <SEP> 24 <SEP> 2 <SEP> BSA <SEP> (0.5) <SEP> DCE <SEP> 92.5 <tb> Example 15 3-(4'-Bromobiphenyl-4-yl)-1,2,3,4-tetrahydro-1-naphthol (7.56g, 0.02M), 4-hydroxycoumarin (6.5g, 0.04M) and p-toluenesulphonic acid (1.9g, 0.01M) were refluxed in 1,2-dichloroethane (130ml) in a Dean-Stark apparatus for 24 hours. The resulting solution was cooled, dichloromethane (150ml) was added, the solution was washed with 5% w/v aqueous sodium carbonate (2x100 ml) and with water (15Qnl), dried (MgSO4) and evaporated to yield a solid residue which was purified by chromatography on silica gel using dichloromethane as eluent to give brodifacoum, 3-[3-(4'-bromobiphenyl-4-yl)1,2,3,4-tetrahydro-1-naphthyl]-4-hydroxycoumarin, (9.7g, 93%) mp 228-2350C. Example 16 The process of Example 15 was followed except that 1,1,2-trichloroethane (20ml) was used in place of the 1,2-dichioroethane, and the reaction mixture was refluxed for 6 hours (not 24 hours). Brodifacoum (8.8g, 84%) mp 228-235 C was oetaened. Example 17 The process of Example 15 was followed except that 3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthol was used in place of the bromo compound, the resulting product being difenacoom, 3-(3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl)-4-hydroxycoumarin, mp 215-2190C, in 95% yield. 18 The process modifications of Example 16 were applied to the process of Example 17. Difenacoum, mp 215-219 C, was obtained in 838 yield. Example 19 The process of Example 17 was followed except that in place of the naphthol was employed 2-biphenyl-4-yl-1,2-dihydro naphthalene. Difenacoum, mp 215-2190C, was obtained in 76% yield. Comparative Example A (in accordance with GB-A-2 126 578, page 10 line 44 to page 11 line 2 and page 7 lines 55 to 59). A mixture of 3(4-(4-trifluoromethylbenzyloxy)phenyl) 1,2,3,4-tetrahydro-1-naphthol (3.9g, 9.8 mmol) and 4-hydroxycoumarin (1.8g, 11.1 mmol) was heated at 160-1700C for one hour After cooling to ambient temperature, the resulting mixture was purified by chromatography on silica gel using dichloranethane as eluant, to give 3-[3-(4- (4-trifluoromethyl- benzyloxy)-phenyl)-1,2,3,4-tetrahydro-1-naphthyl]-4 hydroxycoumarin (2,35g, 44%) m.p. 85-86 C.

Claims: CLAIMS 1. A process for preparing a 4-hydroxycoumarin derivative of formula EMI14.1 wherein R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl of up to 6 carbon atoms and alkoxy of up to 6 carbon atoms, and R3 represents a group selected from EMI14.2 where X represents a halogen atom or a group C1-12 alkyl, C1-12 alkoxy, C3-8 cycloalkyl, CN, SO2R5, CF3, OCF3, COOR5 or COR5, where R5 is C1-6 alkyl, n' is 0, 1 or 2 and Y is a fluorine or chlorine atom; ; EMI14.3 where n' and Y are as defined above, X is as defined above or is hydrogen, nM is 0 or 1 and D is an oxygen atom or a group -O-(CH2)m-, -(CH2)m-O-, -O-(CH2)m-O-, -(CH2)m-O-(CH2)p-, -(CH2)-m, or -CH=CH-, or a sulphur analogue thereof, wherEin m is in the range 1 to 6 and p is in the range 1 to 6; EMI15.1 where X, n' and Y are as defined in (a) above: : (d) a group selected fran EMI15.2 EMI15.3 (e) a group selected fran EMI15.4 where X and n" are as defined in (b) above, A is an oxygen or sulphur atom and D' is an oxygen atom or a -CH2- group, which process comprises condensing 4-hydroxycotnarin with a compound of formula EMI15.5 or the corresponding 1,2-dihydronaphthalene, wherein R1, R2 and R3 are as defined above, and L is a hydroxy group or a halogen atom, in the presence of an organic solvent and a catalyst characterised in that the solvent is selected fran formic acid, a mixture of formic acid and at least one C2-6 aliphatic acid having a boiling temperature at atmospheric pressure in the range 60 C to 1050C and a liquid halogenated hydrocarbon having a boiling temperature of at least 600C, and reaction is effected at a temperature in the range 60 C to the reflux temperature of the reaction mixture. 2. A process according to claim 1 wherein R1 and R2 are both hydrogen. 3. A process according to claim 1 or 2 wherein X is a fluorine, chlorine or branine atom or a group CN, NO2, CF3 or OCF3. 4. A process according to claim 3 wherein X is a chlorine or bromine atom or a group CN or CF3. 5. A process according to claim 1 or 2 wherein R represents a group EMI16.1 wherein n', Y, n" and D are as defined in claim 1 and X is hydrogen or is as defined in claim 3 or 4. 6. A process according to claim 5 wherein R3 represents a group EMI16.2 wherein X, n' Y and n" are as defined in claim 5 and D is an oxygen atom, a group -O-CH2-, -CH2-CH2-, -CH2-CH2-CH2 or -CH=CH-. 7. A process according to claim 6 wherein n' is 0, n" is 0 or 1, D is an oxygen atom or a group CH2 and X is a group CF3, H, CN, or Br. 8. A process according to any of claims 1 to 7, wherein the solvent is a liquid halogenated hydrocarbon having a boiling temperature at atmospheric pressure of at least 600C, the catalyst is a sulphonic acid, and reaction is effected at a temperature in the range 600C to the reflux temperature of the reaction mixture. 9. A process according to claim 8 wherein the liquid halogenated hydrocarbon is a chlorinated alkane. 10. A process according to claims 8 or 9 wherein the liquid halogenated hydrocarbon is selected fran C2-4 di- and trichloroalkanes. 11. A process according to claim 10 wherein the liquid halogenated hydrocarbon is selected fran 1,2-dichloroethane, 1,1,2-trichloroethane, and 1, 3-dichloroprcpne. 12. A process according to any of claims 1 to 11 wherein the catalyst is selected fran rtethanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid.

Inventors: BOEHM, PETER, ENTWISTLE, IAN DAVID
Applicants: SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ B.V.
Application year: 1985
Main classification: C07D311
IPC codes: C07D311, C07D409, A61P7, A61K31, C07B61, C07D407, C07D405, B01J27